Tropane derivatives useful in therapy

ABSTRACT

The present invention provides compounds of formula (I)  
                 
 
     wherein X, Y, R 1 , R 2  and R 3  are as defined hereinabove.  
     The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.

[0001] This application claims priority from United Kingdom applicationnumber 0208071.1 filed Apr. 8, 2002, United Kingdom application number0301575.7 filed Jan. 23, 2003, U.S. Provisional application No.60/386,670 filed Jun. 4, 2002, and U.S. Provisional application No.60/449,064 filed Feb. 20, 2003 and incorporates each application byreference in its entirety.

FIELD OF INVENTION

[0002] This invention relates to tropane derivatives, to processes fortheir preparation, to compositions containing them and to their use.

[0003] More particularly, the present invention relates to the use of8-azabicyclo[3.2.1]octane derivatives in the treatment of a variety ofdisorders, including those in which the modulation of chemokine CCR5receptors is implicated. Accordingly, compounds of the invention areuseful in the treatment of HIV, such as HIV-1, and genetically relatedretroviral infections (and the resulting acquired immune deficiencysyndrome, AIDS), and inflammatory diseases.

[0004] The name “chemokine”, is a contraction of “chemotacticcytokines”. The chemokines comprise a large family of proteins whichhave in common important structural features and which have the abilityto attract leukocytes. As leukocyte chemotactic factors, chemokines playan indispensable role in the attraction of leukocytes to various tissuesof the body, a process which is essential for both inflammation and thebody's response to infection. Because chemokines and their receptors arecentral to the pathophysiology of inflammatory and infectious diseases,agents which are active in modulating, preferably antagonizing, theactivity of chemokines and their receptors, are useful in thetherapeutic treatment of such inflammatory and infectious diseases.

[0005] The chemokine receptor CCR5 is of particular importance in thecontext of treating inflammatory and infectious diseases. CCR5 is areceptor for chemokines, especially for the macrophage inflammatoryproteins (MIP) designated MIP-1α and MIP-1β, and for a protein which isregulated upon activation and is normal T-cell expressed and secreted(RANTES).

[0006] According to a first aspect of the present invention, there isprovided a compound of formula (I)

[0007] or a pharmaceutically acceptable salt, solvate of derivativethereof, wherein:

[0008] X and Y are selected from CH₂ and NR⁴ such that one of X and Y isCH₂ and the other is NR⁴;

[0009] R¹ and R⁴ are independently R⁵; COR⁵; CO₂R⁵; CONR⁶R⁷; SO₂R⁵; or(C₁₋₆ alkylene)phenyl, wherein phenyl is substituted by 0 to 3 atoms orgroups selected from C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁶R⁷, COR⁷, CO₂R⁷ or CONR⁶R⁷;

[0010] R² is phenyl substituted by 0 to 3 atoms or groups selected fromC₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,halogen, CF₃, OH, CN, NR⁶R⁷, CO₂R⁷ or CONR⁶ R⁷;

[0011] R³ is C₁₋₄ alkyl substituted by 0 to 3 fluorine atoms;

[0012] R⁵ is C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₃₋₇ cycloalkyl; a5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturatedheterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl aresubstituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃,OR⁷, CN, NR⁶R⁷, COR⁷, CO₂R⁷ or CONR⁶R⁷; wherein said heterocylcescontain one to three heteroatoms selected from N, O or S; and whereinsaid heterocylces are substituted by 0 to 3 atoms or groups selectedfrom C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,halogen, CF₃, OH, CN, NR⁶R⁷, COR⁷, CO₂R⁷ or CONR⁶R⁷;

[0013] R⁶ is H or R⁵;

[0014] R⁷ is H or C₁₋₆ alkyl;

[0015] or, when R⁶ and R⁷ are both attached to the same N atom, NR⁶R⁷may also represent a 5 to 7 membered, saturated, partially unsaturatedor aromatic, heterocycle containing from 0 to 2 additional heteroatomsselected from O, N or S.

[0016] In one aspect of the invention X is CH₂, NH, NC₁₋₄ alkyl,NCH₂phenyl, NCOC₁₋₄ alkyl substituted by 0 to 3 fluorine atoms, NCO₂C₁₋₄alkyl or NSO₂C₁₋₂ alkyl.

[0017] In another aspect of the invention X is CH₂, NCOC₁₋₂ alkylsubstituted by 0 or 3 fluorine atoms, or NCO₂C₁₋₄ alkyl.

[0018] In another aspect of the invention X is CH₂, NCOC₁₋₂ alkyl orNCO₂C₁₋₂ alkyl.

[0019] In another aspect of the invention Y is CH₂, NH, NC₁₋₆ alkyl,N(C₁₋₆ alkylene)phenyl, NCOC₁₋₆ alkyl substituted by 0 to 3 fluorineatoms, NCO₂C₁₋₆ alkyl or NSO₂C₁₋₆ alkyl.

[0020] In another aspect of the invention Y is CH₂, NH, NC₁₋₄ alkyl,N(C₁₋₄ alkylene)phenyl, NCOC₁₋₄ alkyl substituted by 0 to 3 fluorineatoms, NCO₂C₁₋₄ alkyl or NSO₂C₁₋₄ alkyl.

[0021] In another aspect of the invention Y is CH₂, NH, NCOC₁₋₄ alkyl,NCH₂phenyl, NCOC₁₋₄ alkyl substituted by 0 or 3 fluorine atoms, NCO₂C₁₋₄alkyl or NSO₂C₁₋₂ alkyl.

[0022] In another aspect of the invention Y is CH₂, NCOC₁₋₂ alkyl, orNCO₂C₁₋₂ alkyl.

[0023] In one aspect of the invention R¹ is COR⁵ or CO₂R⁵ and R⁵ is,C₁₋₆ alkyl substituted by 0 to 3 fluorine atoms, C₃₋₇ cycloalkylsubstituted by 0 to 3 fluorine atoms, C₁₋₆ alkoxy substituted by 0 to 3fluorine atoms, or a 4 to 7-membered saturated heterocycle containing 1to 3 heteroatoms selected from N, O or S.

[0024] In another aspect of the invention R¹ is COR⁵ or CO₂R⁵, whereinR⁵ is C₁₋₄ alkyl substituted by 0 to 3 fluorine atoms, C₃₋₅ cycloalkylsubstituted by 0 to 3 fluorine atoms, or a 5 or 6-membered, N, O or Scontaining, saturated heterocycle.

[0025] In another aspect of the invention R¹ is COR⁵ or CO₂R⁵ and R⁵ isC₁₋₃ alkyl substituted by 0 or 3 fluorine atoms, C₃₋₄ cycloalkyl, or a 5or 6-membered, O-containing, saturated heterocycle.

[0026] In another aspect of the invention R¹ is COC₁₋₂ alkyl or CO₂C₁₋₂alkyl.

[0027] In another aspect of the invention R² is phenyl substituted by 0to 3 fluorine atoms.

[0028] In another aspect of the invention R² is phenyl substituted by 0or 1 fluorine atoms.

[0029] In another aspect of the invention R² is unsubstituted phenyl.

[0030] In another aspect of the invention R² is mono-fluoro-substituted(e.g. meta substituted) phenyl.

[0031] In another aspect of the invention R³ is C₁₋₄ alkyl.

[0032] In another aspect of the invention R³ is methyl.

[0033] The term “alkyl” as a group or part of a group includes straightchain and branched groups. Examples of alkyl include methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. The term“C₃₋₇ cycloalkyl” means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl. The term halogen means fluoro, chloro, bromo or iodo.

[0034] It is to be understood that the invention covers all combinationsof particular aspects of the invention as described hereinabove,consistent with the definition of compounds of formula (I).

[0035] The compounds of formula (I) contain at least two basic centresand suitable acid addition salts are formed from acids which formnon-toxic salts. Examples include the hydrochloride, hydrobromide,hydroiodide, chloride, bromide, iodide, sulphate, bisulphate, nitrate,phosphate, hydrogen phosphate, acetate, fumarate, pamoate, aspartate,besylate, carbonate, bicarbonate, camsylate, D and L-lactate, D andL-tartrate, esylate, mesylate, malonate, orotate, gluceptate,methylsulphate, stearate, glucuronate, 2-napsylate, tosylate, hibenzate,nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate,saccharate, benzoate, esylate, and pamoate salts. For a review onsuitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.

[0036] The pharmaceutically acceptable solvates of the compounds offormula (I) or salts or derivatives thereof include the hydratesthereof.

[0037] The compounds of formula (I) may be modified to providepharmaceutically acceptable derivatives thereof at any of the functionalgroups in the compounds. It will be appreciated by those skilled in theart that certain protected derivatives of compounds of formula (I),which may be made prior to a final deprotection stage, may not possesspharmacological activity as such, but may, in certain instances, betransformed after administration into or onto the body, for example bymetabolism, to form compounds of formula (I) which are pharmacologicallyactive. Such derivatives are included in the term “prodrug”. It willfurther be appreciated by those skilled in the art that certain moietiesknown to those skilled in the art as “pro-moieties”, for example asdescribed in “Design of Prodrugs” by H Bundgaard (Elsevier) 1985, may beplaced on appropriate functionalities in compounds of formula (I), alsoto form a “prodrug”. Further, certain compounds of formula (I) may actas prodrugs of other compounds of formula (I). By pharmaceuticallyacceptable derivatives of a compound of formula (I) is meant allprotected derivatives, and prodrugs, of the compounds of formula (I).

[0038] Also included within the present scope of the compounds offormula (I) are polymorphs thereof.

[0039] It will be appreciated by the skilled artisan that the compoundsof formula (I) may contain an additional chiral centre and thereforeexist in two or more stereoisomeric forms. It will be furtherappreciated by the skilled artisan that imidazole substitution of thetropane ring can be in either endo- or exo-configuration, and it is tobe understood that the present invention covers both configurations. Thepresent invention includes all the individual stereoisomers (e.g.enantiomers) of the compounds of formula (I) and, where appropriate, theindividual tautomeric forms thereof, together with mixtures (e.g.racemic mixtures) thereof.

[0040] Imidazole substitution of the tropane ring in theendo-configuration is preferred.

[0041] Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography orH.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or asuitable salt or derivative thereof. An individual enantiomer of acompound of formula (I) may also be prepared from a correspondingoptically pure intermediate or by resolution, such as by H.P.L.C. of thecorresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate. Alternatively, an individual enantiomer of a compound offormula (I) may be prepared by employing chiral reagents, such as chiralcatalysts.

[0042] The invention also includes isotopically labelled compounds offormula (I). An isotopic variation of a compound of the formula (I) or apharmaceutically acceptable salt, solvate or derivative thereof isdefined as one in which at least one atom is replaced by an atom havingthe same atomic number but an atomic mass different from the atomic massusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the formula (I) and pharmaceutically acceptable salts,solvates and derivatives thereof include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.Certain isotopic variations of the compounds of the formula (I) andpharmaceutically acceptable salts, solvates and derivatives thereof, forexample, those in which a radioactive isotope such as ³H or ¹⁴C isincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements and hence may be preferred in some circumstances. Isotopicvariations of the compounds of formula (I) and pharmaceuticallyacceptable salts, solvates and derivatives thereof of this invention canbe prepared by appropriate adaptation of the general methods discussedhereinafter and the processes illustrated by the Preparations andExamples that follow.

[0043] Preferred compounds of formula (I) include the compounds ofExamples 7, 13, 17, 27, 29, 33, 34, 35, 36, 37, 39, 41, 44/45, 46, 49;and pharmaceutically acceptable salts, solvates or derivatives thereof.

[0044] Compounds of formula (I) and pharmaceutically acceptable salts,solvates and derivatives thereof and intermediates thereto may beprepared by any method known in the art for the preparation of compoundsof analogous structure, such as the methods described in WO00/38680 andWO01/90106, both publications incorporated herein by reference. Inparticular, the reaction conditions described in WO01/90106 for thepreparation of compounds of formula (I) from compounds of formulae(XIV), (XIX) and (XXIV) therein, are suitable for use in, respectively,processes, (G), (K) and (L) herein.

[0045] In the general processes, and schemes, that follow: R¹ to R⁷, Xand Y are as previously defined unless otherwise stated; R⁸ and R^(8a)in formula (III.2), process (B), are such that the group

[0046] defines the desired R⁵ substituent, wherein the arrow indicatesthe point of attachment to the compound of formula (II); Z is H, or acarboxylic acid activating group such as chloro or 1H-imidazol-1-yl;EsGp is an ester-forming group, such as C₁₋₆ alkyl; Pg is an aminoprotecting group, such as boc; ArLg is a leaving group appropriate toaromatic nucleophilic substitution, such as those disclosed in JerryMarch, Advanced Organic Chemistry (4th edition), Wiley Interscience,1992, page 652 (incorporated herein by reference), e.g. F, Cl, Br, OMeor OEt; boc is t-butoxycarbonyl; DMF is N,N-dimethylformamide; DCM isdichloromethane;. THF is tetrahydrofuran; Lg is a leaving groupappropriate to aliphatic nucleophilic substitution, such as thosedisclosed in Jerry March, ibid, page 352 (incorporated herein byreference), including Cl, Br, I and sulfonic esters (e.g. tosylate,mesylate and triflate); WSCDI is1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCC isN,N′-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole;HOBt is 1-hydroxybenzotriazole hydrate; PyBOP® isbenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate;PyBrOP is bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; andMukaiyama's reagent is 2-chloro-1-methylpyridinium iodide.

[0047] Compounds of formula (I) may be prepared by the following generalprocesses.

[0048] According to a first process (A) compounds of formula (I) whereinR¹ is R⁵ may be prepared by alkylating a compound of formula (II)

[0049] with a compound of formula (III.1), R⁵Lg (III.1), underconventional alkylating conditions. Conveniently, alkylation is effectedunder the conditions described hereinafter in connection with scheme 1,step (i).

[0050] According to a second process (B) compounds of formula (I)wherein R¹ is R⁵ may be prepared by reacting a compound of formula (II)with a compound of formula (III.2), R⁸R^(8a)C═O (III.2), underconventional conditions of reductive amination. Conveniently, reductiveamination is effected under the conditions described hereinafter inconnection with scheme 1, step (g).

[0051] According to a third process (C) compounds of formula (I) whereinR¹ is COR⁵ may be prepared by reacting a compound of formula (II) with acompound of formula (III.3):

[0052] under conventional carboxylic acid/amine coupling conditions.Conveniently, the coupling is effected under the conditions describedhereinafter in connection with scheme 1, step (k).

[0053] According to a fourth process (D) compounds of formula (I)wherein R¹ is CO₂R⁵ may be prepared by reacting a compound of formula(II) with a haloformate of formula (III.4)

[0054] under conventional coupling conditions. Conveniently, thereaction is effected under the conditions described hereinafter inconnection with scheme 1 for the preparation of compounds of formula(IV) wherein R⁴ is CO₂R⁵.

[0055] According to a fifth process (E) compounds of formula (I) whereinR¹ is CONR⁶R⁷ may be prepared by reacting an amine of formula (II) withan acylimidazolide of formula (III.5)

[0056] under conventional conditions. Conveniently, the reaction iseffected under the conditions described hereinafter in connection withscheme 1 for the preparation of compounds of formula (IV) wherein R⁴ isCONR⁶R⁷.

[0057] According to a sixth process (F) compounds of formula (I) whereinR¹ is SO₂R⁵ may be prepared by reacting a compound of formula (II) witha sulphonylhalide of formula (III.6)

[0058] under conventional conditions. Conveniently, the reaction iseffected under the conditions described hereinafter in connection withscheme 1 for the preparation of compounds of formula (IV) wherein R⁴ isSO₂R⁶.

[0059] According to another process (G) compounds of formula (I) may beprepared by reduction of a compound of formula (XVII)

[0060] under conventional reduction conditions.

[0061] According to another process (H) compounds of formula (I) may beprepared by reductive amination of an aldehyde of formula (XVIII)

[0062] with an amine of formula (XIX)

[0063] under conventional conditions. Conveniently, reductive aminationis effected under the conditions described hereinafter in connectionwith scheme 1, step (g).

[0064] According to another process (I) compounds of formula (I) may beprepared by reductive amination of a nitrile of formula (XX)

[0065] with an amine of formula (XIX) under conventional conditions.Conveniently, reductive amination is effected under the conditionsdescribed hereinafter in connection with scheme 1, step (g).

[0066] According to another process (J) compounds of formula (I) may beprepared by alkylation of an amine of formula (XIX) or a salt thereofwith a compound of formula (XXI)

[0067] under conventional conditions. Conveniently, alkylation iseffected under the conditions described hereinafter in connection withscheme 1, step (i).

[0068] According to another process (K) compounds of formula (I) may beprepared by asymmetric reduction of a compound of formula (XXII)

[0069] under conventional reduction conditions.

[0070] According to another process (L) compounds of formula (I) whereinR¹ is COR⁵ may be prepared from the amine of the formula (II), or ametal salt thereof (i.e. a deprotonated form), by reaction with an esterof the formula (XXIII)

R⁵CO₂EsGp  (XXII)

[0071] under conventional conditions.

[0072] According to another process (M) compounds of formula (I) may beprepared by interconversion from another compound of formula (I).Suitable interconversions include the preparation of compounds offormula (I) wherein X or Y is NR⁵ from the corresponding compound offormula (I) wherein X or, respectively, Y, is NH. The skilled artisanwill appreciate that such interconversion can be readily carried outaccording to methods directly analogous to those described above underprocesses (A) to (F), and (L).

[0073] According to another process (N) compounds of formula (I) may beprepared by deprotection of a protected derivative of a compound offormula (I).

[0074] Schemes that further illustrate general methods for thepreparation of compounds of formula (I), and intermediates thereto,follow.

[0075] It will be appreciated by those skilled in the art that certainof the procedures described in the schemes for the preparation ofcompounds of formula (I) or intermediates thereto may not be applicableto some of the possible substituents.

[0076] It will be further appreciated by those skilled in the art thatit may be necessary or desirable to carry out the transformationsdescribed in the schemes in a different order from that described, or tomodify one or more of the transformations, to provide the desiredcompound of formula (I).

[0077] It will be still further appreciated by those skilled in the artthat, as illustrated in the schemes that follow, it may be necessary ordesirable at any stage in the synthesis of compounds of formula (I) toprotect one or more sensitive groups in the molecule so as to preventundesirable side reactions. In particular, it may be necessary ordesirable to protect amino groups. The protecting groups used in thepreparation of compounds of formula (I) may be used in conventionalmanner. See, for example, those described in ‘Protective Groups inOrganic Synthesis’ by Theodora W Green and Peter G M Wuts, thirdedition, (John Wiley and Sons, 1999), in particular chapter 7, pages494-653 (“Protection for the Amino Group”), incorporated herein byreference, which also describes methods for the removal of such groups.

[0078] The amino protecting groups boc, benzyloxycarbonyl, benzyl andacetyl are of particular use in the preparation of compounds of formula(I) and intermediates thereto.

[0079] With specific reference to scheme 1, the transformations depictedtherein may be effected as follows:

[0080] (a) Substitution of a leaving group on a nitropyridine of formula(XV) with an amine of formula (XIV) is conveniently effected in thepresence of a base, such as an amine (e.g. triethylamine orN-ethyl-N,N-diisopropylamine) or an alkali metal carbonate (e.g. sodiumcarbonate or potassium carbonate); in a solvent, such as an alcohol(e.g. methanol or ethanol), a nitrile (e.g. acetonitrile) or an amide(e.g. DMF); and at from ambient to elevated temperature (e.g. up toabout 120° C.).

[0081] (b) An imidazopyridine of formula (XI) may be prepared byreduction and in situ cyclisation of an amino-nitropyridine of formula(XII). The reduction is conveniently effected in the presence of areducing agent, such as iron powder; a solvent, such as a carboxylicacid (e.g. acetic acid); and at from ambient temperature up to about120° C. Cyclisation of the intermediate amino-aminopyridine isconveniently effected by the addition of an anhydride of formula (XIII)and at elevated temperature (e.g. about 140° C.).

[0082] (c) Reduction of an imidazopyridine of formula (XI) to animidazopiperidine of formula (X) is conveniently effected by catalytichydrogenation in the presence of a suitable catalyst, such as atransition metal catalyst, for instance a platinum (e.g. platinum oxide)or a palladium (e.g. palladium hydroxide or palladium on carbon)catalyst; in a solvent, such as a an alcohol (e.g. methanol or ethanol)or a carboxylic acid (e.g. acetic acid); at ambient to elevatedtemperature (e.g. up to 80° C.; and at elevated pressure, such as from150 to 500 kPa of hydrogen (e.g. 400 kPa hydrogen)

[0083] (d) The imidazopiperidine of formula (X) may be protected byreaction with a benzyl halide, such as benzyl bromide or benzylchloride. The reaction is conveniently carried out in a solvent, such asan alcohol (e.g. ethanol) or a haloalkane (e.g. DCM), and at roomtemperature.

[0084] (e) In an alternative to steps (c) and (d), an imidazopyridine offormula (XI) is treated with a benzyl halide, such as benzyl bromide, togive a quaternary intermediate, which is reduced under conventionalconditions. Conveniently, benzyl bromide is added to an imidazopyridineof formula (XI) in the presence of a solvent, such as an alcohol (e.g.ethanol) or a haloalkane (e.g. DCM) and at ambient temperature to give aquaternary intermediate, which is then reduced by the addition of analkali metal halide, such as sodium borohydride, under conditions ofreduced temperature (e.g. about −70° C.).

[0085] (f) Where the protecting group is an acetyl protecting group orlike group, its removal is conveniently effected by treatment with abase, such as an alkali metal hydroxide (e.g. sodium or potassiumhydroxide) or an acid, such as an inorganic acid (e.g. hydrochloricacid) and at elevated temperature, such as from 60-100° C.

[0086] (g) Compounds of formula (VI) are prepared by reductive aminationof an aldehyde of formula (VIII) by an amine of formula (VII).Conveniently, the reaction is carried out in the presence of an acid,such as an organic acid (e.g. acetic acid); in a solvent, such as anether (e.g. THF) or a haloalkane (e.g. DCM); using an alkali metalhydride reducing agent, such as sodium triacetoxyborohydride, sodiumcyanoborohydride or sodium borohydride; and at ambient temperature.

[0087] (h) Where protection under step (d) is afforded by means of abenzyl group, its removal is conveniently effected by transferhydrogenation using a suitable source of hydrogen, such as ammoniumformate, over a transition metal catalyst, such as a palladium catalyst(e.g. palladium on carbon or palladium hydroxide on carbon), in asolvent, such as an alcohol (e.g. ethanol) and at elevated temperature,such as about 60° C.

[0088] (i) When R⁴ is R⁵, compounds of formula (IV) are prepared fromamines of formula (V) by alkylation with a compound of formula (III.1).Conveniently, alkylation is effected in a suitable solvent such as ahaloalkane (e.g. DCM), alcohol (e.g. ethanol) or ether (e.g. THF);optionally in the presence of a base such as triethylamine orN-ethyl-N,N-diisopropylamine; and at from ambient to elevatedtemperature (e.g. reflux).

[0089] (j) Where the protecting group is a boc protecting group, itsremoval is conveniently effected in the presence of an acid, such as aninorganic acid (e.g. anhydrous HCl) or trifluoroacetic acid; in asuitable solvent, such as an ester (e.g. ethyl acetate), haloalkane(e.g. DCM) or ether (e.g. THF); and from 0° C. to ambient temperature.

[0090] (k) Compounds of formula (I) may be prepared from a compound offormula (II) according to processes (A)-(F), and (L), describedhereinabove.

[0091] With reference to process (C), the acid/amine coupling isconveniently effected using an acid chloride of formula (III.3); anexcess of an acid acceptor such as triethylamine orN-ethyl-N,N-diisopropylamine; a solvent, such as a haloalkane (e.g. DCM)or an ether (e.g. THF); and at ambient temperature.

[0092] Alternatively, the acid/amine coupling is effected using an acidof formula (III.3) activated by reagents such as WSCDI or DCC and HOBtor HOAt; an excess of an acid acceptor such as triethylamine orN-ethyl-N,N-diisopropylamine; a solvent, such as a haloalkane (e.g. DCM)or an ether (e.g. THF); and at ambient temperature.

[0093] In a further alternative, the acid/amine coupling is effectedusing an acid of formula (III.3); either PyBOP, PyBrOP or Mukaiyama'sreagent; an excess of an acid acceptor such as triethylamine orN-ethyl-N,N-diisopropylamine; a solvent such as a haloalkane (e.g. DCM)or an ether (e.g. THF); and at ambient temperature.

[0094] It will be appreciated by those skilled in the art that one ormore of the transformations described in the scheme 1 may be carried outin a different order from that described, or may be modified, in orderto provide the desired compound of formula (I).

[0095] In one variation of scheme 1, step (i) may be effected underconditions of reductive amination, such as those described above forstep (g), employing a compound of formula (III.2).

[0096] In another variation of scheme 1, compounds of formula (IV)wherein R⁴ is COR⁵ may be prepared by reacting a compound of formula (V)with a compound of formula (III.3) under conventional carboxylicacid/amine coupling, such as those described above under step (k).

[0097] In another variation of scheme 1, compounds of formula (IV)wherein R⁴ is CO₂R⁵ are prepared by reacting a compound of formula (V)with a haloformate of formula (III.4) (e.g. a chloroformate); optionallywith an acid acceptor, such as triethylamine orN-ethyl-N,N-diisopropylamine; in a solvent, such as a haloalkane (e.g.DCM) or an ether (e.g. THF); and at from 0° C. to ambient temperature.

[0098] In another variation of scheme 1, compounds of formula (IV)wherein R⁴ is CONR⁶R⁷ may be prepared by reacting a compound of formula(V) with an acylimidazolide of formula (III.5); optionally with an acidacceptor, such as triethylamine or N-ethyl-N,N-diisopropylamine; in asolvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and atfrom 0° C. to ambient temperature.

[0099] In another variation of scheme 1, compounds of formula (IV)wherein R⁴ is SO₂R⁵ may be prepared by reacting a compound of formula(V) with a sulphonylhalide of formula (III.6) (e.g. asulphonylchloride); optionally with an acid acceptor, such astriethylamine or N-ethyl-N,N-diisopropylamine; in a solvent, such as ahaloalkane (e.g. DCM); and at from 0° C. to ambient temperature.

[0100] In another variation of scheme 1, compounds of formula (I)wherein X is NR⁴ and Y is CH₂ may be prepared by replacing in step (a)the nitropyridine of formula (XV) with a nitropyridine of formula (XVI)

[0101] The skilled artisan will appreciate, therefore, that thoseformulae in Scheme 1 derived from formula (XV), including formulae (I),(II), (IV), (V), (VI), (VII), (IX), (X), (XI) and (XII), are intended toembrace the corresponding compounds derived formula (XVI).

[0102] In another variation of scheme 1, compounds of formula (I) may beprepared by carrying out steps (h) to (k) in a different order, asillustrated in scheme 1a that follows.

[0103] The skilled artisan will appreciate that the variations discussedjust above, with respect to R⁴ and step (i) of scheme 1, apply just asequally to R¹ and step (k) of scheme 1a. Likewise, with reference to thevariation of scheme 1 discussed just above deriving from formula (XVI),the skilled artisan will appreciate that those formulae in Scheme 1aderived from formula (XV), including formulae (I), (VI), (XXIV), (XXV)and (XXVI), are intended to embrace the corresponding compounds derivedformula (XVI).

[0104] Moreover, the skilled artisan will further appreciate thatprocesses (A) to (F), and (L), have direct counterparts in respect ofthe preparation of compounds of formula (I) from a compound of formula(XXIV) wherein, respectively, R¹ is: R⁵, COR⁵, CO₂R⁵, CONR⁶R⁷ and SO₂R⁵.

[0105] Compounds of formulae (XVII), (XIX) and (XXII) are of analogousstructure to compounds of formula (I), or intermediates thereto, and maybe prepared by analogous methods.

[0106] Compounds of formulae (III.1) to (III.6), (VIII), (XIII) to(XVI), (XVIII), (XX), and (XXI) are either known compounds or may beprepared by conventional chemistry; see, for example: WO01/90106.

[0107] A pharmaceutically acceptable salt of a compound of the formula(I) may be readily prepared by mixing together solutions of a compoundof the formula (I) and the desired acid. The salt may precipitate fromsolution and be collected by filtration or may be recovered byevaporation of the solvent.

[0108] The compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and derivatives are useful because they havepharmacological activity in animals, including humans. Moreparticularly, they are useful in the treatment of a disorder in whichthe modulation of CCR5 receptors is implicated. Disease states ofparticular interest include HIV, retroviral infections geneticallyrelated to HIV, AIDS, and inflammatory diseases.

[0109] The compounds of this invention may be used for treatment ofrespiratory disorders, including adult respiratory distress syndrome(ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonarydisease, cystic fibrosis, asthma, emphysema, rhinitis and chronicsinusitis.

[0110] Other conditions that may be treated are those triggered,affected or are in any other way correlated with T-cell trafficking indifferent organs. It is expected that the compounds of this inventionmay be useful for the treatment of such conditions and in particular,but not limited to the following for which a correlation with CCR5 orCCR5 chemokines has been established: inflammatory bowel disease,including Crohn's disease and ulcerative colitis, multiple sclerosis,rheumatoid arthritis, graft rejection, in particular but not limited tosolid organ translplasnts, such as heart, lung, liver, kidney andpancreas transplants (e.g. kidney and lung allografts), endometriosis,type I diabetes, renal diseases, such as glomerular disease, fibrosis,such as liver, pulmonary and renal fibosis, chronic pancreatitis,inflammatory lung conditions, encephalitis, such as HIV encephalitis,chronic heart failure, psoriasis, stroke, obesity, CNS diseases, such asAIDS related dementias and Alzheimer's Disease, anaemia, atheroscleroticplaque, atopic dermatitis, chronic pancreatitis, cancer, such asnon-Hodgkin's lymphoma, Kaposi's sarcoma, melanoma and breast cancer,and pain, such as nociceptive pain and neuropathic pain (e.g. peripheralneuropathic pain).

[0111] Infectious diseases where modulation of the CCR5 receptor isimplicated include acute and chronic hepatitis B Virus (HBV) and HCVinfection, bubonic, septicemic, and pneumonic plague, pox virusinfection, such as smallpox, toxoplasmosis infection, mycobacteriuminfection, trypanosomal infection such as Chagas' Disease, pneumonia,and cytosporidiosis.

[0112] For a recent review of possible applications of chemokines andchemokine receptor blockers see Cascieri, M. A., and Springer, M. S.,“The chemokine/chemokine receptor family: potential and progress fortherapeutic intervention”, Curr. Opin. Chem. Biol., 4(4), 420-7 (August2000).

[0113] The utility of the compounds of formula (I) and theirpharmaceutically acceptable salts, solvates and derivatives asinhibitors of HIV infection may be demonstrated by any one or moremethodologies known in the art, such as by using the HIV microcultureassays described in Dimitrov et al., J. Clin. Microbiol., 28, 734-737(1990), and the pseudotyped HIV reporter assay described in Connor etal., Virology, 206 (2) 935-44 (1995).

[0114] The ability of the compounds of formula (I) and theirpharmaceutically acceptable salts, solvates and derivatives to modulatechemokine receptor activity is demonstrated by methodology known in theart, such as: by using the assay for CCR5 binding following proceduresdisclosed in Combadiere et al., J. Leukoc. Biol., 60, 147-52 (1996); byusing the intracellular calcium mobilisation assays as described by thesame authors; and by their ability to inhibit binding of HIV envelopeprotein (gp 120) to CCR5 receptors according to the procedure describedin Example 1 of EP 1 118 858 A2 (pp 85-88). Cell lines expressing thereceptor of interest include those naturally expressing the receptor,such as PM-1, or IL-2 stimulated peripheral blood lymphocytes (PBL), ora cell engineered to express a recombinant receptor, such as CHO,300.19, L1.2 or HEK-293.

[0115] The compounds of the formula (I) can be administered alone butwill generally be administered in admixture with a suitablepharmaceutical excipient, diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice.

[0116] For example, the compounds of the formula (I) can be administeredorally, buccally or sublingually in the form of tablets, capsules,multi-particulates, gels, films, ovules, elixirs, solutions orsuspensions, which may contain flavouring or colouring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications. The compounds of the formula (I) mayalso be administered as fast-dispersing or fast-dissolving dosage formsor in the form of a high energy dispersion or as coated particles.Suitable formulations of the compounds of the formula (I) may be incoated or uncoated form, as desired.

[0117] Such solid pharmaceutical compositions, for example, tablets, maycontain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate, glycine andstarch (preferably corn, potato or tapioca starch), disintegrants suchas sodium starch glycollate, croscarmellose sodium and certain complexsilicates, and granulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

GENERAL EXAMPLE

[0118] A formulation of the tablet could typically contain from 0.01 mgto 500 mg of active compound whilst tablet fill weights may range from50 mg to 1000 mg. Examples of formulations for, respectively, 5 and 10mg tablets are illustrated below: Ingredient % w/w Compound of theformula (I)* 5.000 Avicel PH102 60.500 DCP Anhydrous 30.500 Explotab CLV3.000 Magnesium Stearate¹ 1.000 Compound of the formula (I)* 10.000Lactose 64.125 Starch 21.375 Croscarmellose sodium 3.000 Magnesiumstearate 1.500

[0119] The tablets are manufactured by a standard process, for example,direct compression or a wet or dry granulation process. The tablet coresmay be coated with appropriate overcoats, such as Opadry White/OpadryClear, and are suitable packaged (e.g. in bottles or blister packs).

[0120] Solid compositions of a similar type may also be employed asfillers in gelatin or HPMC capsules. Preferred excipients in this regardinclude lactose, starch, a cellulose, milk sugar or high molecularweight polyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the formula (I) may be combined with various sweetening orflavouring agents, colouring matter or dyes, with emulsifying and/orsuspending agents and with diluents such as water, ethanol, propyleneglycol and glycerin, and combinations thereof.

[0121] The compounds of the formula (I) can also be administeredparenterally, for example, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrally,intrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion or needleless injection techniques.For such parenteral administration they are best used in the form of asterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

[0122] For oral or parenteral administration to human patients the dailydosage levels of compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and derivatives will be from 0.01 to 30 mg/kg(in single or divided doses) and preferably will be in the range 0.01 to15 mg/kg. Thus tablets will contain 1 mg to 0.5 g of compound foradministration singly or two or more at a time, as appropriate. Thephysician in any event will determine the actual dosage which will bemost suitable for any individual patient and it will vary with the age,weight and response of the particular patient. The above dosages areexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited and such arewithin the scope of this invention.

[0123] Oral administration is preferred. Preferably, administrationtakes place shortly before an effect is required.

[0124] The compounds of formula (I) can also be administeredintranasally or by inhalation and are conveniently delivered in the formof a dry powder inhaler or an aerosol spray presentation from apressurised container, pump, spray, atomiser or nebuliser, with orwithout the use of a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray, atomiser or nebulisermay contain a solution or suspension of the active compound, e.g. usinga mixture of ethanol and the propellant as the solvent, which mayadditionally contain a lubricant, e.g. sorbitan trioleate. Capsules andcartridges (made, for example, from gelatin) for use in an inhaler orinsufflator may be formulated to contain a powder mix of a compound ofthe formula (I) and a suitable powder base such as lactose or starch.

[0125] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 1 μg to 10 mg of acompound of the formula (I) for delivery to the patient. The overalldaily dose with an aerosol will be in the range of from 1 μg to 20 mgwhich may be administered in a single dose or, more usually, in divideddoses throughout the day.

[0126] Alternatively, the compounds of the formula (I) can beadministered in the form of a suppository or pessary, or they may beapplied topically in the form of a gel, hydrogel, lotion, solution,cream, ointment or dusting powder. The compounds of the formula (I) mayalso be dermally or transdermally administered, for example, by the useof a skin patch. They may also be administered by the pulmonary orrectal routes.

[0127] They may also be administered by the ocular route, particularlyfor treating inflammatory conditions or diseases of the eye. Forophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

[0128] For application topically to the skin, the compounds of theformula (I) can be formulated as a suitable ointment containing theactive compound suspended or dissolved in, for example, a mixture withone or more of the following: mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,emulsifying wax and water. Alternatively, they can be formulated as asuitable lotion or cream, suspended or dissolved in, for example, amixture of one or more of the following: mineral oil, sorbitanmonostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

[0129] The compounds of the formula (I) may also be used in combinationwith a cyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

[0130] The compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and derivatives have the advantage that theyare more selective, have a more rapid onset of action, are more potent,are better absorbed, are more stable, are more resistant to metabolism,have a reduced ‘food effect’, have an improved safety profile or haveother more desirable properties (e.g. with respect to solubility orhygroscopicity) than the compounds of the prior art.

[0131] The compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and derivatives may be administered alone oras part of a combination therapy. Thus included within the scope of thepresent invention are embodiments comprising coadministration of, andcompositions which contain, in addition to a compound of the presentinvention as active ingredient, additional therapeutic agents and activeingredients. Such multiple drug regimens, often referred to ascombination therapy, may be used in the treatment and prevention of anyof the diseases or conditions mediated by or associated with CCR5chemokine receptor modulation, particularly infection by humanimmunodeficiency virus, HIV. The use of such combinations of therapeuticagents is especially pertinent with respect to the treatment andprevention of infection and multiplication of the human immunodeficiencyvirus, HIV, and related pathogenic retroviruses within a patient in needof treatment or one at risk of becoming such a patient. The ability ofsuch retroviral pathogens to evolve within a relatively short period oftime into strains resistant to any monotherapy which has beenadministered to said patient is well known in the literature.

[0132] In addition to the requirement of therapeutic efficacy, which maynecessitate the use of active agents in addition to the CCR5 chemokinereceptor modulating compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and derivatives, there may be additionalrationales which compel or highly recommend the use of combinations ofdrugs involving active ingredients which represent adjunct therapy,i.e., which complement and supplement the function performed by the CCR5chemokine receptor modulating compounds of the present invention. Suchsupplementary therapeutic agents used for the purpose of auxiliarytreatment include drugs which, instead of directly treating orpreventing a disease or condition mediated by or associated with CCR5chemokine receptor modulation, treat diseases or conditions whichdirectly result from or indirectly accompany the basic or underlyingCCR5 chemokine receptor modulated disease or condition. For example,where the basic CCR5 chemokine receptor modulated disease or conditionis HIV infection and multiplication, it may be necessary or at leastdesirable to treat opportunistic infections, neoplasms, and otherconditions which occur as the result of the immune-compromised state ofthe patient being treated. Other active agents may be used with thecompounds of formula (I) and their pharmaceutically acceptable salts,solvates and derivatives, e.g., in order to provide immune stimulationor to treat pain and inflammation which accompany the initial andfundamental HIV infection.

[0133] Thus, the methods of treatment and pharmaceutical compositions ofthe present invention may employ the compounds of formula (I) and theirpharmaceutically acceptable salts, solvates and derivatives in the formof monotherapy, but said methods and compositions may also be used inthe form of multiple therapy in which one or more compounds of formula(I) or their pharmaceutically acceptable salts, solvates and derivativesare coadministered in combination with one or more known therapeuticagents such as those described in detail further herein.

[0134] Preferred combinations of the present invention includesimultaneous, or sequential treatments with a compound of formula (I),or a pharmaceutically acceptable salt, solvate or derivative thereof,and one or more inhibitors of HIV protease and/or inhibitors of HIVreverse transcriptase, preferably selected from the class ofnon-nucleoside reverse transcriptase inhibitors (NNRTI), including butnot limited to nevirapine, delavirdine and efavirenz; from among thenucleoside/nucleotide inhibitors, including but not limited tozidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir,adefovir and dipivoxil; and from among the protease inhibitors,including but not limited to indinavir, ritonavir, saquinavir,nelfinavir, lopinavir and amprenavir.

[0135] Other agents useful in the above-described preferred embodimentcombinations of the present invention include current andto-be-discovered investigational drugs from any of the above classes ofinhibitors, including but not limited to FTC, PMPA, fozivudine tidoxil,talviraline, S-1153, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690,ABT-378, KNI-764, TMC120 and TMC125.

[0136] There is also included within the scope of the preferredembodiments of the present invention, combinations of a compound offormula (I), or a pharmaceutically acceptable salt, solvate orderivative thereof, together with a supplementary therapeutic agent usedfor the purpose of auxiliary treatment, wherein said supplementarytherapeutic agent comprises one or more members independently selectedfrom the group consisting of proliferation inhibitors, e.g.,hydroxyurea; immunomodulators, e.g., sargramostim, and various forms ofinterferon or interferon derivatives; fusion inhibitors, e.g., AMD3100,T-20, T-1249, PRO-140, PRO-542, AD-349, BB-10010 and other chemokinereceptor agonists/antagonists; tachykinin receptor modulators, e.g. NK1antagonists; integrase inhibitors, e.g., AR177; RNaseH inhibitors;inhibitors of viral transcription and RNA replication; and other agentsthat inhibit viral infection or improve the condition or outcome ofHIV-infected individuals through different mechanisms.

[0137] Preferred methods of treatment of the present invention for theprevention of HIV infection, or treatment of aviremic and asymptomaticsubjects potentially or effectively infected with HIV, include but arenot limited to administration of a member independently selected fromthe group consisting of: (i) a compound within the scope of formula (I)as disclosed herein; (ii) one NNRTI in addition to a compound of (i);(iii) two NRTI in addition to a compound of (i); (iv) one NRTI inaddition to the combination of (ii); and (v) a compound selected fromthe class of protease inhibitors used in place of a NRTI in combinations(iii) and (iv).

[0138] The preferred methods of the present invention for therapy ofHIV-infected individuals with detectable viremia or abnormally low CD4counts further include as a member to be selected: (vi) treatmentaccording to (i) above in addition to the standard recommended initialregimens for the therapy of established HIV infections, e.g., seehttp://hivatis.org/trtgdlns.html. Such standard regimens include but arenot limited to an agent from the class of protease inhibitors incombination with two NRTIs; and (vii) a standard recommended initialregimens for the therapy of established HIV infections, e.g., seehttp://hivatis.org/trtgdlns.html, where either the protease inhibitorcomponent, or one or both of the NRTIs is/are replaced by a compoundwithin the scope of formula (I) as disclosed herein.

[0139] The preferred methods of the present invention for therapy ofHIV-infected individuals that have failed antiviral therapy furtherinclude as a member to be selected: (viii) treatment according to (i)above, in addition to the standard recommended regimens for the therapyof such patients, e.g., see http://hivatis.org/trtgdlns.html; and (ix) astandard recommended initial regimens for the therapy of patients whohave failed antiretroviral therapy, e.g., seehttp://hivatis.org/trtgdlns.html, where either one of the proteaseinhibitor components, or one or both of the NRTIs is/are replaced by acompound within the scope of formula (I) as disclosed herein.

[0140] Additional combinations for use according to the inventioninclude combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or derivative thereof with another CCR5antagonist, such asN-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-4,4-difluorocyclohexanecarboxamide;a CCR1 antagonist, such as BX-471; a beta adrenoceptor agonist, such assalmeterol; a corticosteroid agonist, such fluticasone propionate; aLTD4 antagonist, such as montelukast; a muscarinic antagonist, such astiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast;a COX-2 inhibitor, such as celecoxib, valdecoxib or rofecoxib; analpha-2-delta ligand, such as gabapentin or pregabalin; abeta-interferon, such as REBIF; a TNF receptor modulator, such as aTNF-alpha inhibitor (e.g. adalimumab), a HMG CoA reductase inhibitor,such as a statin (e.g. atorvastatin); or an immunosuppressant, such ascyclosporin or a macrolide such as tacrolimus.

[0141] In the above-described preferred embodiment combinations of thepresent invention, the compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or derivative thereof and other therapeuticactive agents may be administered in terms of dosage forms eitherseparately or in conjunction with each other, and in terms of their timeof administration, either serially or simultaneously. Thus, theadministration of one component agent may be prior to, concurrent with,or subsequent to the administration of the other component agent(s).

[0142] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment.

[0143] Thus the invention provides:

[0144] a compound of formula (I) or a pharmaceutically acceptable salt,solvate or derivative thereof;

[0145] processes for the preparation of a compound of formula (I) or apharmaceutically acceptable salt, solvate or derivative thereof;

[0146] a pharmaceutical composition including a compound of formula (I)or a pharmaceutically acceptable salt, solvate or derivative thereof,together with a pharmaceutically acceptable excipient, diluent orcarrier;

[0147] a compound of formula (I) or a pharmaceutically acceptable salt,solvate or derivative thereof, for use as a medicament;

[0148] a compound of formula (I) or a pharmaceutically acceptable salt,solvate or derivative thereof, for the treatment of a disorder in whichthe modulation of CCR5 receptors is implicated;

[0149] a compound of formula (I) or a pharmaceutically acceptable salt,solvate or derivative thereof, for the treatment of HIV, a retroviralinfection genetically related to HIV, AIDS, or an inflammatory disease;

[0150] a compound of formula (I) or a pharmaceutically acceptable salt,solvate or derivative thereof, for the treatment of a respiratorydisorder including adult respiratory distress syndrome (ARDS),bronchitis, chronic bronchitis, chronic obstructive pulmonary disease,cystic fibrosis, asthma, emphysema, rhinitis or chronic sinusitis;

[0151] a compound of formula (I) or a pharmaceutically acceptable salt,solvate or derivative thereof, for the treatment of an inflammatorybowel disease, including Crohn's disease or ulcerative colitis, multiplesclerosis, rheumatoid arthritis, graft rejection, including a kidney ora lung allograft, endometriosis, type I diabetes, a renal disease,chronic pancreatitis, an inflammatory lung condition or chronic heartfailure;

[0152] the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate or derivative thereof, for the manufacture of amedicament for the treatment of a disorder in which the modulation ofCCR5 receptors is implicated;

[0153] the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate or derivative thereof, for the manufacture of amedicament for the treatment of HIV, a retroviral infection geneticallyrelated to HIV, AIDS, or an inflammatory disease;

[0154] the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate or derivative thereof, for the manufacture of amedicament for the treatment of a respiratory disorder including adultrespiratory distress syndrome (ARDS), bronchitis, chronic bronchitis,chronic obstructive pulmonary disease, cystic fibrosis, asthma,emphysema, rhinitis or chronic sinusitis;

[0155] the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate or derivative thereof, for the manufacture of amedicament for the treatment of an inflammatory bowel disease, includingCrohn's disease or ulcerative colitis, multiple sclerosis, rheumatoidarthritis, graft rejection, including a kidney or a lung allograft,endometriosis, type I diabetes, a renal disease, chronic pancreatitis,an inflammatory lung condition or chronic heart failure;

[0156] a method of treatment of a mammalian disorder in which themodulation of CCR5 receptors is implicated which comprises treating saidmammal with an effective amount of a compound of formula (I) or with apharmaceutically acceptable salt, solvate or derivative thereof;

[0157] a method of treatment of HIV, a retroviral infection geneticallyrelated to HIV, AIDS, or an inflammatory disease which comprisestreating said mammal with an effective amount of a compound of formula(I) or with a pharmaceutically acceptable salt, solvate or derivativethereof;

[0158] a method of treatment of a respiratory disorder including adultrespiratory distress syndrome (ARDS), bronchitis, chronic bronchitis,chronic obstructive pulmonary disease, cystic fibrosis, asthma,emphysema, rhinitis or chronic sinusitis which comprises treating saidmammal with an effective amount of a compound of formula (I) or with apharmaceutically acceptable salt, solvate or derivative thereof;

[0159] a method of treatment of an inflammatory bowel disease, includingCrohn's disease or ulcerative colitis, multiple sclerosis, rheumatoidarthritis, graft rejection, including a kidney or a lung allograft,endometriosis, type I diabetes, a renal disease, chronic pancreatitis,an inflammatory lung condition or chronic heart failure which comprisestreating said mammal with an effective amount of a compound of formula(I) or with a pharmaceutically acceptable salt, solvate or derivativethereof; and

[0160] intermediates of the formulae (II), (IV), (V), (VI), (VII), (IX),(X), (XI), (XVII), (XIX), (XXII), (XXIV), (XXV), and (XXVI); thecorresponding intermediates obtained by replacing in step (a) thenitropyridine of formula (XV) with a nitropyridine of formula (XVI); andthe corresponding deprotected derivatives thereof.

[0161] The invention is illustrated by the following Examples andPreparations in which the following further abbreviations may be used:

[0162] 0.88 ammonia=concentrated ammonium hydroxide solution, 0.88 SG

[0163] h=hour

[0164] min=minute

[0165] MS=mass spectrum

[0166] NMR=nuclear magnetic resonance

[0167] Me=methyl

Example 1N-{(1S)-3-[3-endo-(5-Benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide

[0168]

[0169] Acetyl chloride (0.3 ml, 4.20 mmol) was added to a solution of(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine(Preparation 13) (1.8 g, 3.84 mmol) dissolved in dichloromethane (30 ml)under nitrogen at room temperature. The reaction was stirred at roomtemperature for 2 hours, and the solvent was removed under reducedpressure. The residue was purified by flash column chromatography onsilica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.8 then 90:10:1). Product containing fractionswere evaporated to afford the title compound as a white foam (1.76 g).

[0170]¹H NMR (400 MHz, CDCl₃): δ: 7.20-7.38 (10H, m), 6.42-6.48 (1H, d),5.05-5.14 (1H, m), 4.23-4.37 (1H, m), 3.68 (2H, s), 3.44 (2H, s),3.19-3.28 (2H, m), 2.81-2.89 (2H, m), 2.63-2.69 (2H, m), 2.31-2.45 (5H,m), 2.13-2.22 (2H, m), 1.82-2.02 (7H, m), 1.26-1.42 (2H, q), 1.14-1.41(2H, m) ppm.

[0171] LRMS (electrospray): m/z [M+Na]⁺ 534, [M+H]⁺ 512, [M−H]⁺ 510.

[0172] Found C, 72.92; H, 8.06; N, 13.45. C₃₂H₄₁N₅O. 0.75 mol H₂Orequires C, 73.18; H, 8.16; N, 13.33%.

Example 2N-{(1S)-3-[3-endo-(2-Methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide

[0173]

[0174] 20% Palladium on carbon (0.16 g) was added to a solution ofN-{(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 1) (0.80 g, 1.56 mmol) dissolved in ethanol (20 ml) undernitrogen at room temperature. Ammonium formate (0.40 g, 6.34 mmol) wasthen added and the reaction mixture was gently refluxed for 30 minutes.A further aliquot of ammonium formate (0.20 g, 3.17 mmol) was then addedand the solution gently refluxed for 45 minutes. The reaction mixturewas cooled to room temperature and filtered through Arbocel® washingwell with ethanol. The filtrate was concentrated under reduced pressureand the residue was purified by flash column chromatography on silicagel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (92:8:0.8, byvolume, changing to 90:10:1). Product containing fractions wereevaporated to afford the title compound as a white foam (0.61 g).

[0175]¹H NMR (400 MHz, CDCl₃): δ: 7.20-7.38 (5H, m), 6.26-6.36 (1H, d),5.12-5.19 (1H, m), 4.36-4.46 (1H, m), 3.89 (2H, s), 3.27-3.37 (2H, m),3.03-3.09 (2H, m), 2.52-2.63 (2H, m), 2.31-2.53 (5H, m), 2.17-2.29 (2H,m), 1.89-2.17 (7H, m), 1.40-1.59 (4H, m) ppm.

[0176] LRMS (electrospray): m/z [M+Na]⁺ 444, [M+H]⁺ 422, [M−H]⁺ 420.

[0177] Found C, 67.14; H, 8.29; N, 15.62. C₂₅H₃₅N₅O. 1.5 mol H₂Orequires C, 66.93; H, 8.54; N, 15.61%.

Example 3N-{(1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide

[0178]

[0179] Acetyl chloride (0.015 ml, 0.173 mmol) was added to a solution ofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.066 g, 0.157 mmol) dissolved in dichloromethane (4 ml)under nitrogen at room temperature. The reaction was stirred at roomtemperature for 30 minutes, and the reaction mixture was washed withsaturated aqueous sodium hydrogencarbonate solution (5 ml). The organicphase was dried (MgSO₄) and the solvent was removed under reducedpressure. The residue was purified by flash column chromatography onsilica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.8). Product containing fractions wereevaporated to afford the title compound as a white foam (0.069 g) whichwas a mixture of rotamers.

[0180]¹H NMR (400 MHz, CDCl₃): δ: 7.23-7.40 (5H, m), 6.26-6.31 (0.83H,d), 6.03-6.07 (0.17H, d), 5.18-5.24 (0.17H, q), 5.12-5.18 (0.83H, q),4.64 (2H, s), 4.37-4.59 (1H, m), 3.80-3.85 (0.34H, m), 3.64-3.69 (1.66H,t), 3.31-3.38 (2H, m), 2.60-2.66 (0.34H, m), 2.67-2.73 (1.66H, m),2.38-2.54 (5H, m), 2.20-2.24 (2H, t), 2.18 (3H, s), 2.02-2.17 (2H, m),2.00 (3H, s), 1.93-1.99 (2H, m), 1.42-1.64 (4H, m) ppm.

[0181] LRMS (electrospray): m/z [M+Na]⁺ 486, [M+H]⁺ 464, [M−H]⁺ 462.

Example 4N-{(1S)-3-[3-endo-(5-Isopropyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide

[0182]

[0183] Acetic acid (0.06 ml, 1.04 mmol) was added to a stirred solutionofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.09 g, 0.21 mmol) and acetone (0.03 ml, 0.41 mmol)dissolved in dichloromethane (5 ml) under nitrogen at room temperature.Sodium triacetoxyborohydride (0.09 g, 0.42 mmol) was then added and thereaction was held at room temperature for 18 hours. A further aliquot ofacetone (0.03 ml, 0.41 mmol) and sodium triacetoxyborohydride (0.09 g,0.42 mmol) was added and the reaction stirred at room temperature for afurther 24 hours. The reaction mixture was partitioned between saturatedaqueous sodium hydrogencarbonate solution (10 ml) and dichloromethane(10 ml). The organic phase was removed and the aqueous phase was washedwith dichloromethane (10 ml). The combined organic phases were washedwith H₂O (10 ml), dried (MgSO₄) and the solvent was removed underreduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.8). Product containing fractions wereevaporated to afford the title compound as a white foam (0.066 g).

[0184] hu 1H NMR (400 MHz, CDCl₃): δ: 7.24-7.39 (5H, m), 6.26-6.45 (1H,d), 5.12-5.18 (1H, q), 4.31-4.43 (1H, m), 3.62 (2H, s), 3.29-3.38 (2H,m), 2.88-2.97 (1H, ), 2.75-2.81 (2H, m), 2.58-2.65 (2H, m), 2.41-2.51(2H, m), 2.37 (3H, s), 2.20-2.25 (2H, m), 2.03-2.12 (2H, m), 2.01 (3H,s), 1.91-2.00 (2H, m), 1.47-1.60 (4H, m), 1.11-1.18 (6H, d) ppm.

[0185] LRMS (electrospray): m/z [M+Na]⁺ 486, [M+H]⁺ 464, [M−H]⁺ 462.

[0186] Found C, 69.93; H, 8.92; N, 14.69. C₂₈H₄₁N₅O. 1 mol H₂O requiresC, 69.82; H, 9.00; N, 14.54%.

Example 5N-{(1S)-3-3-endo-(2,5-Dimethyl-4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide

[0187]

[0188] Sodium triacetoxyborohydride (0.50 g, 2.35 mmol) was added to astirred solution ofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.45 g, 1.06 mmol) and paraformaldehyde (0.064 g, 2.13mmol) dissolved in dichloromethane (4 ml) under nitrogen at roomtemperature, and the reaction stirred at room temperature for 18 hours.Further aliquots of paraformaldehyde (0.064 g, 2.13 mmol) and sodiumtriacetoxyborohydride (0.5 g, 2.35 mmol) were added and stirringcontinued for a further 24 hours. The reaction mixture was partitionedbetween saturated aqueous sodium hydrogencarbonate solution (10 ml) anddichloromethane (10 ml). The organic phase was removed and the aqueousphase was washed with dichloromethane (10 ml). The combined organicphases were washed with H₂O (10 ml), dried (MgSO₄) and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (92:8:0.8, byvolume, changing to 90:10:0.5 then 90:10:0.6). Product containingfractions were evaporated to afford the title compound as a white foam(0.10 g).

[0189]¹H NMR (400 MHz, CDCl₃): δ: 7.23-7.38 (5H, m), 6.34-6.39 (1H, d),5.10-5.18 (1H, q), 4.35-4.44 (1H, m), 3.50 (2H, s), 3.31-3.38 (2H, m),2.63-2.73 (4H, m), 2.37-2.51 (8H, m), 2.19-2.25 (2H, t), 1.90-2.16 (9H,m), 1.43-1.60 (2H, m) ppm.

[0190] LRMS (electrospray): m/z [M+H]⁺ 436, [M−H]⁺ 434.

[0191] Found C, 69.17; H, 8.62; N, 15.43. C₂₆H₃₇N₅O. 0.9 mol H₂Orequires C, 69.12; H, 8.66; N, 15.50%.

Example 6N-((1S)-3-{3-endo-[2-Methyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)acetamide

[0192]

[0193] Methanesulfonyl chloride (0.02 ml, 0.25 mmol) was added to asolution ofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.08 g, 0.19 mmol) and triethylamine (0.04 ml, 0.29 mmol)dissolved in dichloromethane (3 ml) under nitrogen at room temperature.The reaction was stirred at room temperature for 18 hours, and thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(94:6:0.6, by volume, changing to 92:8:0.8). Product containingfractions were evaporated to afford the title compound as a pink foam(0.065 g).

[0194]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.43 (5H, m), 6.03-6.11 (1H, d),5.13-5.22 (1H, q), 4.38-4.48 (3H, m), 3.56-3.67 (2H, m), 3.28-3.39 (2H,m), 2.84 (3H, s), 2.70-2.78 (2H, m), 2.38-2.68 (5H, m), 2.18-2.37 (2H,m), 1.90-2.17 (7H, m), 1.52-1.68 (2H, d), 1.39-1.51 (2H, m) ppm.

[0195] LRMS (electrospray): m/z [M+Na]⁺ 522, [M+H]⁺ 500, [M−H]⁺ 498.

[0196] Found C, 60.68; H, 7.50; N, 13.41. C₂₆H₃₇N₅O₃S. 0.75 mol H₂Orequires C, 60.85; H, 7.56; N, 13.65%.

Example 7 Methyl3-endo-{8-[(3S)-3-(acetamido)-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0197]

[0198] Methyl chloroformate (0.02 ml, 0.25 mmol) was added to a solutionofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.08 g, 0.19 mmol) and triethylamine (0.04 ml, 0.29 mmol)dissolved in dichloromethane (3 ml) under nitrogen at room temperature.The reaction was stirred at room temperature for 18 hours, and thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(94:6:0.6, by volume, changing to 92:8:0.8). Product containingfractions were evaporated to afford the title compound as an off-whitefoam (0.075 g).

[0199]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.40 (5H, m), 6.22-6.32 (1H, m),5.10-5.17 (1H, m), 4.47-4.57 (2H, m), 4.37-4.47 (1H, m), 3.64-3.76 (5H,m), 3.29-3.37 (2H, m), 2.59-2.66 (2H, m), 2.42-2.54 (2H, m), 2.38(3H,s), 2.18-2.28 (2H, m), 1.92-2.15 (7H, m), 1.43-1.60 (4H, m) ppm.

[0200] LRMS (electrospray): m/z [M+H]⁺ 480, [M−H]⁺ 478.

[0201] Found C, 65.92; H, 7.91; N, 14.20. C₂₇H₃₇N₅O₃. 0.75 mol H₂Orequires C, 65.76; H, 7.87; N, 14.20%.

Example 8N-{(1S)-3-[3-endo-(2-Methyl-5-propionyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl[-1-phenylproyl}acetamide

[0202]

[0203] Propionyl chloride (0.02 ml, 0.23 mmol) was added to a solutionofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.08 g, 0.19 mmol) and triethylamine (0.04 ml, 0.29 mmol)dissolved in dichloromethane (3 ml) under nitrogen at room temperature.The reaction was stirred at room temperature for 18 hours and thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(94:6:0.6, by volume, changing to 92:8:0.8). Product containingfractions were evaporated to afford the title compound as a white foam(0.078 g) which was a mixture of rotamers.

[0204]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.38 (5H, m), 6.28-6.36 (0.8H,d), 6.03-6.08 (0.2H, d), 5.10-5.18 (1H, q), 4.66 (2H, s), 4.37-4.43 (1H,m), 3.82-3.86 (0.4H, m), 3.64-3.73 (1.6H, t), 3.28-3.39 (2H, m),2.58-2.72 (2H, m), 2.32-2.52 (7H, m), 2.18-2.28 (2H, t), 2.02-2.16 (2H,m), 1.92-2.01 (5H, m), 1.47-1.64 (4H, m), 1.15-1.20 (3H, t) ppm.

[0205] LRMS (electrospray): m/z [M+Na]⁺ 500, [M+H]⁺ 478, [M−H]⁺ 476.

[0206] Found C, 68.72; H, 8.30; N, 14.29. C₂₈H₃₉N₅O₂. 0.75 mol H₂Orequires C, 68.47; H, 8.31; N, 14.26%.

Example 9N-{(1S)-3-[3-endo-(5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide

[0207]

[0208] Isobutyryl chloride (0.025 ml, 0.24 mmol) was added to a solutionofN-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.08 g, 0.19 mmol) and triethylamine (0.04 ml, 0.29 mmol)dissolved in dichloromethane (3 ml) under nitrogen at room temperature.The reaction was stirred at room temperature for 18 hours and thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(94:6:0.6, by volume, changing to 92:8:0.8). Product containingfractions were evaporated to afford the title compound as a white foam(0.078 g) which was a mixture of rotamers.

[0209]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.38 (5H, m), 6.28-6.34 (0.9H,d), 6.03-6.09 (0.1H, m), 5.18-5.25 (0.1H, m), 5.09-5.17 (0.9H, q), 4.67(2H, s), 4.52-4.61 (0.1H, m), 4.38-4.52 (0.9H, m), 3.79-3.86 (0.2H, m),3.70-3.77 (1.8H, t), 3.26-3.37 (2H, m), 2.58-2.74 (2H, m), 2.35-2.50(5H, m), 2.16-2.28 (2H, t), 2.02-2.15 (2H, m), 1.98 (3H, s), 1.87-1.97(2H, m), 1.45-1.65 (4H, m), 1.10-1.20 (6H, d) ppm.

[0210] LRMS (electrospray): m/z [M+Na]⁺ 514, [M+H]⁺ 492, [M−H]⁺ 490.

[0211] Found C, 69.57; H, 8.53; N, 14.08. C₂₉H₄₁N₅O₂. 0.5 mol H₂Orequires C, 69.57; H, 8.46; N, 13.99%.

Example 10N-{(1S)-3-[3-endo-(2,5-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclobutanecarboxamide

[0212]

[0213] Cyclobutylcarbonyl chloride (0.03 ml, 0.26 mmol) was added to asolution of(1S)-3-[3-endo-(2,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine(Preparation 14) (0.085 g, 0.22 mmol) and triethylamine (0.04 ml, 0.29mmol) dissolved in dichloromethane (3 ml) under nitrogen at roomtemperature. The reaction was stirred at room temperature for one hour,and the solvent was removed under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (94:6:0.6, by volume, changing to 92:8:0.8 then 90:10:1).Product containing fractions were evaporated to afford the titlecompound as a white foam (0.089 g).

[0214]¹H NMR (400 MHz, CDCl₃): δ: 7.21-7.37 (5H, m), 6.01-6.07 (1H, d),5.08-5.15 (1H, q), 4.32-4.43 (1H, m), 3.52 (2H, s), 3.25-3.37 (2H, m),2.92-3.02 (1H, m), 2.62-2.73 (4H, m), 2.36-2.50 (8H, m), 2.00-2.34 (8H,m), 1.82-1.99 (4H, m), 1.42-1.58 (4H, m) ppm.

[0215] LRMS (electrospray): m/z [M+H]⁺ 476, [M−H]⁺ 474.

[0216] Found C, 71.94; H, 8.79; N, 14.46. C₂₉H₄₁N₅O. 0.5 mol H₂Orequires C, 71.87; H, 8.73; N, 14.45%.

Example 11N-{(1S)-3-[3-endo-(2,5-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}tetrahvdropyran-4-carboxamide

[0217]

[0218] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05g, 0.26 mmol) was added to a solution of tetrahydropyran-4-carboxylicacid (0.03 g, 0.23 mmol),(1S)-3-[3-endo-(2,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine(Preparation 14) (0.08 g, 0.20 mmol), triethylamine (0.04 ml, 0.29 mmol)and 1-hydroxybenzotriazole (0.04 g, 0.26 mmol) dissolved indichloromethane (3 ml) under nitrogen at room temperature. The reactionwas stirred at room temperature for 18 hours, and the reaction mixturethen partitioned between dichloromethane (10 ml) and saturated aqueoussodium hydrogencarbonate solution (10 ml). The organic phase was dried(MgSO₄) and the solvent was removed under reduced pressure. The residuewas purified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (94:6:0.6, by volume, changing to 92:8:0.8 then 90:10:1).Product containing fractions were evaporated to afford the titlecompound as a white foam (0.098 g).

[0219]¹H NMR (400 MHz, CDCl₃): δ: 7.33-7.39 (2H, m), 7.23-7.32 (3H, m),5.88-5.96 (1H, d), 5.08-5.17 (1H, q), 4.35-4.43 (1H, m), 3.97-4.03 (2H,m), 3.48 (2H, s), 3.26-3.44 (4H, m), 2.68-2.73 (2H, m), 2.62-2.68 (2H,m), 2.47 (3H, s), 2.27-2.44 (6H, m), 2.17-2.22 (2H, t), 2.01-2.07 (2H,m), 1.93-2.00 (2H, m), 1.68-1.82 (2H, m), 1.43-1.56 (4H, m) ppm.

[0220] LRMS (electrospray): m/z [M+H]⁺ 506.

[0221] Found C, 69.41; H, 8.64; N, 13.50. C₃₀H₄₃N₅O. 0.75 mol H₂Orequires C, 69.40; H, 8.64; N, 13.49%.

Example 12N-((1S)-3-{3-endo-2-Methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)acetamide

[0222]

[0223] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05g, 0.26 mmol) was added to a solution of 3,3,3-trifluoropropanoic acid(0.027 g, 0.21 mmol),N-{(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}acetamide(Example 2) (0.08 g, 0.19 mmol), triethylamine (0.04 ml, 0.29 mmol) and1-hydroxybenztriazole (0.04 g, 0.26 mmol) dissolved in dichloromethane(3 ml) under nitrogen at room temperature. The reaction mixture wasstirred at room temperature for 18 hours, and then partitioned betweendichloromethane (10 ml) and saturated aqueous sodium hydrogencarbonatesolution (10 ml). The organic phase was dried (MgSO₄) and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol (92:8, by volume, changing to 90:10, 85:15 then80:200). Product containing fractions were evaporated to afford thetitle compound as a white foam (0.089 g).

[0224]¹H NMR (400 MHz, CDCl₃): δ: 7.21-7.39 (5H, m), 6.17-6.31 (1H, m),5.10-5.18 (1H, q), 4.71 (2H, s), 4.46-4.83 (1H, m) 3.65-3.75 (2H, m),3.26-3.48 (4H, m), 2.70-2.76 (1.5H, m), 2.63-2.69 (0.5H, m), 2.44-2.48(2H, m), 2.42 (0.66H, s), 2.41 (2.33H, s), 2.20-2.37 (2H, m), 1.92-2.19(7H, m), 1.59-1.62 (2H, m), 1.45-1.61 (2H, m) ppm.

[0225] LRMS (electrospray): m/z [M+Na]⁺ 554, [M+H]⁺ 532, [M−H]⁺ 530.

[0226] Found C, 60.96; H, 6.80; N, 12.65. C₂₈H₃₆F₃N₅O₂. 1 mol H₂Orequires C, 61.19; H, 6.97; N, 12.74%.

Example 13 Methyl3-endo-{8-[(3S)-3-(acetamido)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0227]

[0228] Acetyl chloride (0.026 g, 0.34 mmol) was added to a solution ofmethyl3-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 21) (0.14 g, 0.31 mmol) and N-ethyl-N,N-diisopropylamine(0.043 g, 0.34 mmol) dissolved in dichloromethane (16 ml) under nitrogenat room temperature. The reaction was stirred at room temperature for 18hours and quenched with saturated aqueous sodium hydrogencarbonatesolution (20 ml). The product was extracted from the organic phase with2N HCl (3×3 ml) and the aqueous phase was basified to pH 10 using 2NNaOH. This was then extracted with dichloromethane (3×5 ml) and thecombined organic extracts were dried (MgSO₄). The solvent was removedunder reduced pressure to afford the title compound as an off-whitesolid (0.132 g).

[0229]¹H NMR (400 MHz, CDCl₃): δ: 7.23-7.31 (1H, m), 7.02-7.08 (1H, d),6.88-6.97 (2H, m), 6.43-6.49 (1H, d), 5.08-5.15 (1H, m), 4.43-4.58 (2H,m), 4.32-4.42 (1H, m), 3.72 (3H, s), 3.58-3.68 (2H, m), 3.25-3.36 (2H,m), 2.57-2.63 (2H, m), 2.39-2.52 (2H, m), 2.37 (3H, s), 2.16-2.23 (2H,t), 1.97-2.12 (5H, m), 1.83-1.96 (2H, m), 1.41-1.63 (4H, m) ppm.

[0230] LRMS (electrospray): m/z [M+H]⁺ 498, [M−H]⁺ 496.

Example 14 Methyl3-endo-{8-[(3S)-3-[(cyclobutylcarbonyl)amino]-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0231]

[0232] Cyclobutylcarbonyl chloride (0.04 g, 0.34 mmol) was added to asolution of methyl3-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 21) (0.14 g, 0.31 mmol) and N-ethyl-N,N-diisopropylamine(0.043 g, 0.34 mmol) dissolved in dichloromethane (16 ml) under nitrogenat room temperature. The reaction was stirred at room temperature for 18hours and quenched with saturated aqueous sodium hydrogencarbonatesolution (20 ml). The product was extracted from the organic phase with2N HCl (3×3 ml) and the aqueous phase was basified to pH 10 using 2NNaOH. This was then extracted with dichloromethane (3×5 ml) and thecombined organic extracts were dried (MgSO₄). The solvent was removedunder reduced pressure to afford the title compound as an off-whitesolid (0.132 g).

[0233]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.32 (1H, m), 7.00-7.05 (1H, m),6.87-6.99 (2H, m), 6.04-6.16 (1H, m), 5.03-5.15 (1H, m), 4.45-4.56 (2H,m), 4.32-4.44 (1H, m), 3.57-3.75 (5H, m), 3.24-3.35 (2H, m), 2.92-3.02(1H, m), 2.56-2.64 (2H, m), 2.34-2.52 (5H, m), 1.98-2.32 (6H, m),1.79-1.96 (4H, m), 1.40-1.67 (6H, m) ppm.

[0234] LRMS (electrospray): m/z [M+H]⁺ 538, [M−H]⁺ 536.

Example 15 Methyl3-endo-(8-{(3S)-3-(3-fluorophenyl)-3-[(3,3,3-trifluoropropanoyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0235]

[0236] 3,3,3-Trifluoropropanoic acid (0.043 g, 0.34 mmol),1-hydroxybenzotriazole (0.056 g, 0.37 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.076 g,0.4 mmol) and methyl3-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 21) (0.14 g, 0.31 mmol) were dissolved in dichloromethane(16 ml) under nitrogen at room temperature. The reaction was stirred atroom temperature for 18 hours and quenched with saturated aqueous sodiumhydrogencarbonate solution (20 ml). The organic phase was removed anddried (MgSO₄). The solvent was removed under reduced pressure to affordthe title compound as an off-white solid (0.136 g).

[0237]¹H NMR (400 MHz, CDCl₃): δ: 7.23-7.32 (1H, m), 7.02-7.07 (1H, d),6.92-6.97 (2H, m), 6.57-6.69 (1H, m), 5.14-5.22 (1H, m), 4.45-4.56 (2H,m), 4.12-4.23 (1H, m), 3.60-3.72 (5H, m), 3.26-3.36 (2H, m), 2.99-3.14(2H, q), 2.56-2.62 (2H, m), 2.38-2.50 (2H, m), 2.37 (3H, s), 2.18-2.28(2H, m), 2.01-2.13 (2H, m), 1.82-1.99 (2H, m), 1.41-1.65 (4H, m) ppm.

[0238] LRMS (electrospray): m/z [M+H]⁺ 566, [M−H]⁺ 564.

Example 16 Methyl3-endo-(8-{(3S)-3-(3-fluorophenyl)-3-[(methoxycarbonyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4.5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0239]

[0240] Methyl chloroformate (0.032 g, 0.34 mmol) was added to a solutionof methyl3-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 21) (0.14 g, 0.31 mmol) and N-ethyl-N,N-diisopropylamine(0.043 g, 0.34 mmol) dissolved in dichloromethane (16 ml) under nitrogenat room temperature. The reaction was stirred at room temperature for 18hours and quenched with saturated aqueous sodium hydrogencarbonatesolution (20 ml). The organic phase was removed and dried (MgSO₄). Thesolvent was removed under reduced pressure to afford the title compoundas an off-white solid (0.125 g).

[0241]¹H NMR (400 MHz, CDCl₃): δ: 7.32-7.42 (1H, m), 7.23-7.32 (1H, m),7.00-7.05 (1H, d), 6.95-7.00 (1H, d), 6.86-6.95 (1H, t), 4.82-4.92 (1H,m), 4.36-4.60 (3H, m), 3.58-3.73 (8H, m), 3.36-3.45 (1H, m), 3.23-3.32(1H, m), 2.46-2.63 (4H, m), 2.39 (3H, s), 2.18-2.24 (2H, m), 1.92-2.18(4H, m), 1.45-1.76 (4H, m) ppm.

[0242] LRMS (electrospray): m/z [M+H]⁺ 514, [M−H]⁺ 512.

Example 17 Methyl(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate

[0243]

[0244] Methyl chloroformate (0.033 g, 0.35 mmol) was added to a solutionof(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylamine(Preparation 20) (0.14 g, 0.2 mmol) and N-ethyl-N,N-diisopropylamine(0.045 g, 0.35 mmol) dissolved in dichloromethane (16 ml) under nitrogenat room temperature. The reaction was stirred at room temperature for 18hours and quenched with saturated aqueous sodium hydrogencarbonatesolution (10 ml). The product was extracted from the organic phase with2N HCl (3×3 ml) and the aqueous phase was basified to pH 10 using 2NNaOH. This was then extracted with dichloromethane (3×5 ml) and thecombined organic extracts were dried (MgSO₄). The solvent was removedunder reduced pressure to afford the title compound as an off-whitesolid (0.133 g).

[0245]¹H NMR (400 MHz, CDCl₃): δ: 7.33-7.43 (1H, m), 7.23-7.30 (1H, m),7.01-7.05 (1H, d), 6.93-6.99 (1H, d), 6.86-6.91 (1H, t), 4.82-4.92 (1H,m), 4.65 (2H, s), 4.37-4.52 (1H, m), 3.56-3.66 (5H, m), 3.36-3.46 (1H,m), 3.25-3.36 (1H, m), 2.45-2.63 (2H, t), 2.40 (3H, s), 2.18-2.26 (2H,t), 2.15 (3H, s), 1.91-2.10 (2H, m), 1.49-1.77 (6H, m) ppm.

[0246] LRMS (electrospray): m/z [M+H]⁺ 498, [M−H]⁺ 496.

Example 18N-[(1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl]cyclobutanecarboxamide

[0247]

[0248] Cyclobutylcarbonyl chloride (0.041 g, 0.35 mmol) was added to asolution of(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylamine(Preparation 20) (0.14 g, 0.2 mmol) and N-ethyl-N,N-diisopropylamine(0.045 g, 0.35 mmol) dissolved in dichloromethane (16 ml) under nitrogenat room temperature. The reaction was stirred at room temperature for 18hours and quenched with saturated aqueous sodium hydrogencarbonatesolution (10 ml). The product was extracted from the organic phase with2N HCl (3×3 ml) and the aqueous phase was basified to pH 10 using 2NNaOH. This was then extracted with dichloromethane (3×5 ml) and thecombined organic extracts were dried (MgSO₄). The solvent was removedunder reduced pressure to afford the title compound as a white foam(0.124 g) which was a mixture of rotamers.

[0249]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.29 (1H, m), 7.02-7.07 (1H, d),6.87-6.97 (2H, m), 6.09-6.13 (0.83H, d), 5.82-5.86 (0.17H, d), 5.15-5.22(0.17H, m), 5.03-5.13 (0.83H, m), 4.62 (2H, s), 4.35-4.57 (1H, m),3.73-3.87 (0.34H, m), 3.60-3.67 (1.66H, t), 3.25-3.34 (2H, m), 2.90-3.00(1H, m), 2.55-2.68 (2H, m), 2.35-2.51 (5H, m), 2.00-2.25 (13H, m),21.80-1.98 (2H, m), 1.56-1.67 (2H, m), 1.40-1.56 (2H, m) ppm.

[0250] LRMS (electrospray): m/z [M+H]⁺ 522, [M−H]⁺ 520.

Example 19N-[(1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl]-3,3,3-trifluoropropanamide

[0251]

[0252] 3,3,3-Trifluoropropanoic acid (0.045 g, 0.35 mmol),1-hydroxybenzotriazole (0.058 g, 0.38 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.079 g,0.41 mmol) and(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylamine(Preparation 20) (0.140 g, 0.31 mmol) were dissolved in dichloromethane(16 ml) under nitrogen at room temperature. The reaction was stirred atroom temperature for 18 hours and quenched with saturated aqueous sodiumhydrogencarbonate solution (20 ml). The organic phase was removed anddried (MgSO₄). The solvent was removed under reduced pressure to affordthe title compound as an off-white solid (0.136 g) which was a mixtureof rotamers.

[0253]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.33 (1H, m), 7.02-7.07 (1H, d),6.92-6.98 (2H, m), 6.66-6.72 (0.85H, d), 6.36-6.42 (0.15H, d), 5.27-5.34(0.15H, m), 5.13-5.19 (0.85H, m), 4.61 (2H, s), 4.35-4.53 (1H, m),3.68-3.88 (0.3H, m), 3.60-3.66 (1.7H, t), 3.25-3.37 (2H, m), 2.62-2.67(1.7H, m), 2.53-2.61 (0.3H, m), 2.35-2.50 (5H, m), 2.17-2.25 (2H, m),2.13 (3H, s), 2.00-2.11 (2H, m), 1.82-1.99 (2H, m), 1.56-1.65 (2H, m),1.40-1.57 (2H, m) ppm.

[0254] LRMS (electrospray): m/z [M+H]⁺ 550, [M−H]⁺ 548.

Example 20N-[(1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl]tetrahydro-pyran-4-carboxamide

[0255]

[0256] Tetrahydropyran-4-carboxylic acid (0.046 g, 0.35 mmol),1-hydroxybenzotriazole (0.058 g, 0.38 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.079 g,0.41 mmol) and(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylamine(Preparation 20) (0.14 g, 0.31 mmol) were dissolved in dichloromethane(16 ml) under nitrogen at room temperature. The reaction was stirred atroom temperature for 18 hours and quenched with saturated aqueous sodiumhydrogencarbonate solution (20 ml). The organic phase was removed anddried (MgSO₄). The solvent was removed under reduced pressure to affordthe title compound as an off-white solid (0.145 g) which was a mixtureof rotamers.

[0257]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.35 (1H, m), 7.02-7.08 (1H, m),6.88-7.01 (2H, m), 5.93-6.04 (0.85H, d), 5.75-5.82 (0.15H, d), 5.16-5.25(0.15H, m), 5.04-5.15 (0.85H, q), 4.62 (2H, s), 4.33-4.57 (1H, m),3.92-4.02 (2H, m), 3.73-3.89 (0.3H, m), 3.60-3.71 (1.7H, m), 3.22-3.42(4H, m), 2.36-2.48 (2H, m), 2.23-2.57 (7H, m), 2.12-2.23 (5H, m),1.97-2.10 (2H, m), 1.84-1.96 (2H, m), 1.39-1.84 (7H, m) ppm.

[0258] LRMS (electrospray): m/z [M+H]⁺ 552, [M−H]⁺ 550.

Example 21N-((1S)-3-{3-endo-[2-Methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)tetrahydro-pyran-4-carboxamide

[0259]

[0260] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.035 g, 0.18 mmol) was added to a solution oftetrahydropyran-4-carboxylic acid (0.022 g, 0.17 mmol),(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylamine(Preparation 24) (0.075 g, 0.15 mmol), triethylamine (0.03 ml, 0.22mmol) and 1-hydroxybenzotriazole (0.027 g, 0.18 mmol) dissolved indichloromethane (3 ml) under nitrogen at room temperature and stirredfor 18 hours. The solvent was removed under reduced pressure and theresidue was purified by flash column chromatography on silica geleluting with a solvent gradient of dichloromethane:methanol:concentratedaqueous ammonia (95:5:0.5, by volume, changing to 92:8:0.5). Productcontaining fractions were evaporated to afford the title compound as awhite foam (0.075 g) which was a mixture of rotamers.

[0261]¹H NMR (400 MHz, CDCl₃): δ: 7.32-7.38 (2H, m), 7.23-7.32 (3H, m),5.82-5.89 (0.85H, d), 5.66-5.72 (0.15H, d), 5.39-5.45 (0.15H, m),5.11-5.17 (0.85H, q), 4.70 (1.7H, s), 4.67 (0.3H, s), 4.39-4.55 (1H, m),3.93-4.04 (2H, m), 3.72-3.80 (0.3H, m), 3.65-3.71 (1.7H, m), 3.25-3.43(6H, m), 2.62-2.74 (2H, m), 2.15-2.50 (8H, m), 2.00-2.13 (2H, m),1.85-2.00 (2H, m), 1.64-1.84 (4H, m), 1.43-1.63 (4H, m) ppm.

[0262] LRMS (electrospray): m/z [M+H]⁺ 602, [M−H]⁺ 600.

[0263] Found C, 62.85; H, 7.10; N, 11.42. C₃₂H₄₂F₃N₅O₃. 0.5 mol H₂Orequires C, 62.93; H, 7.10; N, 11.47%.

Example 223,3,3-Trifluoro-N-((1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)propanamide

[0264]

[0265] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.035 g, 0.18 mmol) was added to a solution of 3,3,3-trifluoropropanoicacid (0.022 g, 0.17 mmol),(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylamine(Preparation 24) (0.075 g, 0.15 mmol), triethylamine (0.03 ml, 0.22mmol) and 1-hydroxybenzotriazole (0.027 g, 0.18 mmol) dissolved indichloromethane (3 ml) under nitrogen at room temperature and stirredfor 18 hours. The solvent was removed under reduced pressure and theresidue was purified by flash column chromatography on silica geleluting with a solvent gradient of dichloromethane:methanol:concentratedaqueous ammonia (95:5:0.5, by volume, changing to 92:8:0.5). Productcontaining fractions were evaporated to afford the title compound as awhite foam (0.075 g) which was a mixture of rotamers.

[0266]¹H NMR (400 MHz, CDCl₃): δ: 7.32-7.38 (2H, m), 7.22-7.31 (3H, m),6.39-6.47 (0.8H, d), 6.08-6.18 (0.2H, d), 5.51-5.59 (0.2H, q), 5.18-5.25(0.8H, q), 4.70 (1.6H, s), 4.66 (0.4H, s), 4.40-4.55 (1H, m), 4.06-4.16(0.2H, m), 3.63-3.71 (1.8H, t), 3.25-3.36 (4H, m), 3.00-3.14 (2H, m),2.58-2.72 (2H, m), 2.36-2.50 (5H, m), 2.18-2.35 (2H, m), 2.01-2.17 (2H,m), 1.94-2.01 (2H, m), 1.43-1.63 (4H, m) ppm.

[0267] LRMS (electrospray): m/z [M+H]⁺ 600, [M−H]⁺ 598.

[0268] Found C, 57.51; H, 5.91; N, 11.47. C₂₉H₃₅F₆N₅O₂. 0.25 mol H₂Orequires C, 57.66; H, 5.92; N, 11.59%.

Example 23N-((1S)-3-{3-endo-[2-Methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclobutanecarboxamide

[0269]

[0270] Cyclobutylcarbonyl chloride (0.02 ml, 0.17 mmol) was added to asolution of(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylamine(Preparation 24) (0.075 g, 0.15 mmol) and triethylamine (0.03 ml, 0.22mmol) dissolved in dichloromethane (3 ml) under nitrogen at roomtemperature. The reaction was stirred at room temperature for 1.5 hours,and the solvent was removed under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (95:5:0.5, by volume, changing to 92:8:0.5). Product containingfractions were evaporated to afford the title compound as a white foam(0.068 g) which was a mixture of rotamers.

[0271]¹H NMR (400 MHz, CDCl₃): δ: 7.32-7.39 (2H, m), 7.22-7.31 (3H, m),5.86-5.93 (0.87H, d), 5.60-5.64 (0.13H, d), 5.36-5.43 (0.13H, m),5.09-5.16 (0.87H, q), 4.72 (1.8H, s), 4.69 (0.2H, s), 4.39-4.56 (1H, m),3.64-3.71 (2H, t), 3.25-3.36 (4H, m), 2.93-3.03 (1H, m), 2.62-2.75 (2H,m), 2.34-2.52 (5H, m), 2.00-2.33 (8H, m), 1.82-2.00 (4H, m), 1.41-1.61(4H, m) ppm.

[0272] LRMS (electrospray): m/z [M−H]⁺ 570.

[0273] Found C, 64.30; H, 7.11; N, 12.02. C₃₁H₄₀F₃N₅O₂. 0.5 mol H₂Orequires C, 64.12; H, 7.12; N, 12.06%.

Example 24 Methyl(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylcarbamate

[0274]

[0275] Methyl chloroformate (0.015 ml, 0.19 mmol) was added to asolution of(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylamine(Preparation 24) (0.075 g, 0.15 mmol) and triethylamine (0.03 ml, 0.22mmol) dissolved in dichloromethane (3 ml) under nitrogen at roomtemperature. The reaction was stirred at room temperature for 1.5 hours,and the solvent was removed under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (95:5:0.5, by volume, changing to 92:8:0.5). Product containingfractions were evaporated to afford the title compound as a white foam(0.062 g).

[0276]¹H NMR (400 MHz, CDCl₃): δ: 7.33-7.40 (2H, m), 7.21-7.33 (3H, m),7.04-7.18 (1H, m), 4.82-4.96 (1H, m), 4.73 (2H, s), 4.43-4.60 (1H, m),3.64-3.73 (1H, t), 3.46-3.64 (4H, m), 3.39-3.47 (1H, m), 3.26-3.38 (3H,m), 2.62-2.77 (2H, m), 2.49-2.59 (2H, m), 2.43 (3H, s), 2.19-2.30 (2H,m), 1.92-2.08 (4H, m), 1.48-1.68 (4H, m) ppm.

[0277] LRMS (electrospray): m/z [M+H]⁺ 548, [M−H]⁺ 546.

[0278] Found C, 60.47; H, 6.68; N, 12.45. C₂₈H₃₆F₃N₅O₃. 0.5 mol H₂Orequires C, 60.42; H, 6.70; N, 12.58%.

Example 25 Methyl3-endo-(8-{(3S)-3-[(methoxycarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0279]

[0280] Methyl chloroformate (0.015 ml, 0.19 mmol) was added to asolution of methyl3-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 26) (0.06 g, 0.14 mmol) and triethylamine (0.03 ml, 0.22mmol) dissolved in dichloromethane (3 ml) under nitrogen at roomtemperature. The reaction was stirred at room temperature for 18 hoursand the solvent was removed under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (94:6:0.6, by volume, changing to 92:8:0.8). Product containingfractions were evaporated to afford the title compound as a white foam(0.058 g).

[0281]¹H NMR (400 MHz, CDCl₃): δ: 7.22-7.38 (6H, m), 4.87-4.94 (1 H, m),4.42-4.63 (3H, m), 3.65-3.75 (5H, m), 3.62 (3H, s), 3.41-3.47 (1H, t),3.28-3.37 (1H, m), 2.60-2.66 (2H, m), 2.49-2.60 (2H, m), 2.43 (3H, s),2.20-2.27 (2H, m), 1.96-2.20 (4H, m), 1.72-1.82 (1H, m), 1.48-1.69 (3H,m) ppm.

[0282] LRMS (electrospray): m/z [M+H]⁺ 496, [M−H]⁺ 494.

[0283] Found C, 64.34; H, 7.66; N, 13.79. C₂₇H₃₇N₅O₄. 0.5 mol H₂Orequires C, 64.26; H, 7.59; N, 13.88%.

Example 26 Methyl2-methyl-3-endo-(8-{(3S)-3-phenyl-3-[(3,3,3-trifluoropropanoyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0284]

[0285] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04g, 0.21 mmol) was added to a solution of 3,3,3-trifluoropropanoic acid(0.015 ml, 0.16 mmol), methyl3-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 26) (0.06 g, 0.14 mmol), triethylamine (0.03 ml, 0.22 mmol)and 1-hydroxybenzotriazole (0.03 g, 0.20 mmol) dissolved indichloromethane (3 ml) under nitrogen at room temperature. The reactionwas held at room temperature for 18 hours. The solvent was removed underreduced pressure and the residue was purified by flash columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.6). Product containing fractions wereevaporated to afford the title compound as a white foam (0.071 g).

[0286]¹H NMR (400 MHz, CDCl₃): δ: 7.28-7.36 (2H, m), 7.22-7.27 (3H, m),6.37-6.50 (1H, d), 5.14-5.23 (1H, m), 4.51 (2H, s), 4.34-4.46 (1H, m),3.60-3.68 (2H, m), 3.70 (3H, s), 3.27-3.33 (2H, m), 2.98-3.10 (2H, m),2.57-2.64 (2H, m), 2.34-2.52 (5H, m), 2.18-2.27 (2H, m), 2.00-2.10 (2H,m), 1.91-2.00 (2H, m), 1.40-1.60 (4H, m) ppm.

[0287] LRMS (electrospray): m/z [M+H]⁺ 548, [M−H]⁺ 546.

[0288] Found C, 59.99; H, 6.69; N, 12.49. C₂₈H₃₆F₃N₅O₃. 0.75 mol H₂Orequires C, 59.93; H, 6.74; N, 12.48%.

Example 27 Methyl(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate

[0289]

[0290] Methyl chloroformate (0.027 ml, 0.35 mmol) was added to asolution of(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine(Preparation 28) (0.125 g, 0.30 mmol) and triethylamine (0.06 ml, 0.43mmol) dissolved in dichloromethane (5 ml) under nitrogen at roomtemperature. The reaction was stirred at room temperature for 1.5 hoursand the solvent was removed under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (94:6:0.6, by volume, changing to 92:8:0.6). Product containingfractions were evaporated to afford the title compound as a white foam(0.125 g).

[0291]¹H NMR (400 MHz, CDCl₃): δ: 7.19-7.34 (5H, m), 7.10-7.18 (1H, m),4.82-4.92 (1H, m), 4.63 (2H, s), 4.40-4.53 (1H, m), 3.57-3.68 (5H, m),3.37-3.44 (1H, m), 3.24-3.35 (1H, m), 2.57-2.68 (2H, m), 2.44-2.56 (2H,m), 2.40 (3H, s), 2.17-2.25 (2H, m), 1.92-2.16 (7H, m), 1.43-1.66 (4H,m) ppm.

[0292] LRMS (electrospray): m/z [M+H]⁺ 480.

[0293] Found C, 66.26; H, 7.87; N, 14.30. C₂₇H₃₇N₅O₃. 0.5 mol H₂Orequires C, 66.37; H, 7.84; N, 14.33%.

Example 28N-{(1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-3,3,3-trifluoropropanamide

[0294]

[0295] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.077 g, 0.4 mmol) was added to a solution of 3,3,3-trifluoropropanoicacid (0.03 ml, 0.34 mmol),(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine(Preparation 28) (0.125 g, 0.3 mmol), triethylamine (0.07 ml, 0.5 mmol)and 1-hydroxybenzotriazole (0.061 g, 0.40 mmol) dissolved indichloromethane (5 ml) under nitrogen at room temperature. The reactionwas held at room temperature for three hours. The solvent was removedunder reduced pressure and the residue was purified by flash columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.6 then 90:10:0.6). Product containingfractions were evaporated to afford the title compound as a white foam(0.14 g) which was a mixture of rotamers.

[0296]¹H NMR (400 MHz, CDCl₃): δ: 7.32-7.40 (2H, m), 7.27-7.31 (3H, m),6.50-6.58 (0.85H, d), 6.27-6.32 (0.15H, d), 5.31-5.58 (0.15H, m),5.17-5.24 (0.85H, q), 4.64 (2H, s), 4.38-4.60 (1H, m), 3.75-3.87 (0.3H,m), 3.63-3.71 (1.7H, t), 3.30-3.39 (2H, m), 3.01-3.13 (2H, m), 2.60-2.64(0.3H, m), 2.64-2.70 (1.7H, t), 2.37-2.52 (5H, m), 2.20-2.30 (2H, t),2.17 (3H, s), 2.01-2.13 (2H, m), 1.92-2.01 (2H, m), 1.45-1.65 (4H, m)ppm.

[0297] LRMS (electrospray): m/z [M+Na]⁺ 554, [M+H]⁺ 532, [M−H]⁺ 530.

[0298] Found C, 62.24; H, 6.90; N, 13.12. C₂₈H₃₆F₃N₅O₂. 0.5 mol H₂Orequires C, 62.21; H, 6.90; N, 12.95%.

Example 29 Methyl1-endo-{8-[(3S)-3-(acetamido)-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0299]

[0300] Acetyl chloride (0.02 g, 0.25 mmol) was added to a solution ofmethyl1-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride (Preparation 36) (0.125 g, 0.23 mmol) andN-ethyl-N,N-diisopropylamine (0.103 g, 0.8 mmol) dissolved indichloromethane (4 ml) under nitrogen at room temperature and thereaction mixture stirred for 18 hours. Dichloromethane (5 ml) was addedand the solution washed with saturated aqueous sodium hydrogencarbonatesolution (10 ml) and brine (10 ml). The organic phase was dried (MgSO₄)and solvent removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(98:2:0.2, by volume, changing to 97:3:0.3). Product containingfractions were evaporated to afford the title compound as a white foam(0.09 g).

[0301]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.25 (5H, m), 6.30-6.20 (1H, d),5.20-5.10 (1H, q), 4.50-4.35 (3H, m), 3.80-3.60 (5H, m), 3.35 (2H, m),2.80-2.60 (2H, m), 2.50-2.40 (5H, m), 2.30-1.90 (7H, m), 1.70-1.45 (6H,m) ppm.

[0302] LRMS (electrospray): m/z [M+H]⁺ 480, [M−H]⁺ 478.

Example 30 Methyl1-endo-(8-{(3S)-3-[(methoxycarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0303]

[0304] Methyl chloroformate (0.024 g, 0.25 mmol) was added to a solutionof methyl1-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride (Preparation 36) (0.125 g, 0.23 mmol) andN-ethyl-N,N-diisopropylamine (0.118 g, 0.91 mmol) dissolved indichloromethane (4 ml) under nitrogen at room temperature and thereaction mixture stirred for 18 hours. Dichloromethane (5 ml) was addedand the solution washed with saturated aqueous sodium hydrogencarbonatesolution (10 ml) and brine (10 ml). The organic phase was dried (MgSO₄)and solvent removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(99:1:0.1, by volume, changing to 98:2:0.2). Product containingfractions were evaporated to afford the title compound as a white foam(0.07 g).

[0305]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.10 (6H, m), 5.00-4.80 (1H, m),4.60-4.40 (3H, m), 3.80-3.60 (8H, m), 3.50-3.30 (2H, m), 2.80-2.65 (2H,m), 2.60-2.40 (5H, m), 2.30-1.95 (6H, m), 1.85-1.50 (4H, m) ppm.

[0306] LRMS (electrospray): m/z [M+H]⁺ 496.

Example 31 Methyl1-endo-(8-{(3S)-3-[(cyclobutylcarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0307]

[0308] Cyclobutylcarbonyl chloride (0.03 g, 0.25 mmol) was added to asolution of methyl1-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride (Preparation 36) (0.125 g, 0.23 mmol) andN-ethyl-N,N-diisopropylamine (0.118 g, 0.91 mmol) dissolved indichloromethane (4 ml) under nitrogen at room temperature and thereaction mixture stirred for 18 hours. Dichloromethane (5 ml) was addedand the solution washed with saturated aqueous sodium hydrogencarbonatesolution (10 ml) and brine (10 ml). The organic phase was dried (MgSO₄)and solvent removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(99:1:0.1, by volume, changing to 98:2:0.2). Product containingfractions were evaporated to afford the title compound as a white foam(0.08 g).

[0309]¹NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (5H, m), 6.10-6.00 (1H, d),5.20-5.10 (1H, q), 4.50-4.35 (3H, m), 3.80-3.60 (5H, m), 3.40-3.30 (2H,m), 3.00 (1H, qu), 2.80-2.65 (2H, m), 2.50-1.50 (21H, m) ppm.

[0310] LRMS (electrospray): m/z [M+H]⁺ 520.

Example 32 Methyl2-methyl-1-endo-(8-{(3S)-3-phenyl-3-[(3,3,3-trifluoropropanoyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0311]

[0312]1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.056g, 0.3 mmol) was added to a solution of 3,3,3-trifluoropropanoic acid(0.022 ml, 0.25 mmol), methyl1-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride (Preparation 36) (0.125 g, 0.23 mmol),N-ethyl-N,N-diisopropylamine (0.16 ml, 0.91 mmol) and1-hydroxybenzotriazole (0.042 g, 0.27 mmol) dissolved in dichloromethane(4 ml) under nitrogen at room temperature. The reaction was held at roomtemperature for two hours. Dichloromethane (5 ml) was added and thesolution washed with saturated aqueous sodium hydrogencarbonate solution(10 ml) and brine (10 ml). The organic phase was dried (MgSO₄) andsolvent removed under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(99:1:0.1, by volume, changing to 98:2:0.2). Product containingfractions were evaporated to afford the title compound as a white foam(0.077 g).

[0313]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.25 (5H, m), 6.60 (1H, d), 5.20(1H, q), 4.50-4.35 (3H, m), 3.80-3.70 (5H, m), 3.35 (2H, m), 3.15-3.00(2H, q), 2.80-2.60 (2H, m), 2.50-2.40 (5H, m), 2.30-1.90 (6H, m),1.65-1.50 (4H, m) ppm.

[0314] LRMS (electrospray): m/z [M+Na]⁺ 570, [M+H]⁺ 548, [M−H]⁺ 546.

Example 33 Methyl1-endo-{8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0315]

[0316] Acetyl chloride (0.062 g, 0.79 mmol) was added to a solution ofmethyl1-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride (Preparation 40) (0.409 g, 0.72 mmol) and triethylamine(0.33 g, 3.25 mmol) dissolved in dichloromethane (10 ml) under nitrogenat room temperature and the reaction mixture stirred for 2 hours. Thesolution was then washed with water (10 ml), 1 N sodium hydroxidesolution (10 ml) and brine (10 ml). The organic phase was separated,dried (MgSO₄) and solvent removed under reduced pressure. The residuewas purified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (99:1:0.1, by volume, changing to 97:3:0.3). Product containingfractions were evaporated to afford the title compound as a white foam(0.24 g).

[0317]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.25 (1H, m), 7.10-6.90 (3H, m),6.80-6.50 (1H, m), 5.20-5.10 (1H, q), 4.65-4.38 (3H, m), 3.80-3.60 (5H,m), 3.50-3.30 (2H, m), 2.80-1.90 (16H, m), 1.70-1.40 (4H, m) ppm.

[0318] LRMS (electrospray): m/z [M+H]⁺ 498.

[0319] Examples 34-43 were prepared by analogous methods to thosedescribed above. LRMS was by electro-spray. ¹H NMR LRMS Example No. andstructure (400 MHz, CDCl₃) m/z Example 34 7.30-7.25 (1H, m), 512

7.10-6.90 (3H, m), 6.60-6.40 (1H, m), 5.20-5.10 (1H, q), 4.65-4.38 (3H,m), 3.80-3.60 (5H, m), 3.50-3.30 (2H, m), 2.80-1.90 (15H, m), 1.70-1.50(4H, m), 1.2 (3H, t) [M + H]⁺ Example 35 7.40-7.25 (1H, m), 512

7.10-6.90 (4H, m), 5.00-4.80 (1H, m), 4.65-4.40 (3H, m), 4.20-3.65 (4H,m), 3.55-3.30 (2H, m), 2.85-1.50 (20H, m), 1.40-1.00 (3H, m) [M + H]⁺Example 36 7.35-7.25 (1H, m), 498

7.10-6.90 (3H, m), 5.00-4.80 (1H, m), 4.65-4.40 (3H, m), 3.95-3.85 (2H,t), 3.75-3.62 (5H, m), 3.55-3.30 (2H, m), 2.85-1.55 (20H, m) [M + H]⁺Example 37 7.40-7.30 (1H, m), 513

7.10-6.90 (3H, m), 6.65-6.45 (1H, m), 4.65-4.40 (3H, m), 4.17 (2H, q),3.80-3.70 (2H, m), 3.45-3.35 (2H, m), 2.80-1.90 (16H, m), 1.70-1.55 (4H,m), 1.25 (3H, t) [M + H]⁺ Example 38 7.40-7.30 (1H, m), 526

7.05 (1H, d), 7.05-6.90 (2H, m), 6.70-6.50 (1H, m), 5.20-5.05 (1H, m),4.95 (1H, m), 4.65-4.30 (3H, m), 3.80-3.60 (2H, m), 3.45-3.25 (2H, m),2.75-2.60 (2H, m), 2.60-2.35 (5H, m), 2.35-2.20 (2H, m), 2.20-2.00 (5H,m), 2.00-1.85 (2H, m), 1.75-1.45 (4H, m), 1.25 (6H, d) [M + H]⁺ Example39 7.40-7.30 (1H, m), 512

7.05 (1H, d), 7.05-6.90 (2H, m), 6.75-6.50 (1H, m), 520-5.05 (1H, m),4.65-4.40 (3H, m), 4.20 (2H, q), 3.80-3.60 (2H, m), 3.50-3.30 (2H, m),2.75-2.60 (2H, m), 2.60-2.45 (2H, m), 2.40 (3H, s), 2.35-2.20 (2H, m),2.20-1.85 (7H, m), 1.75-1.45 (4H, m), 1.25 (3H, t) [M + H]⁺ Example 407.40-7.30 (1H, m), 526

7.05 (1H, d), 7.05-6.90 (2H, m), 6.65-6.40 (1H, br s), 5.15-5.05 (1H,m), 4.65-4.35 (3H, m), 4.16 (2H, q), 3.80-3.60 (2H, m), 3.50-3.30 (2H,m), 2.75-1.80 (15H, m), 1.80-1.40 (4H, m), 1.25 (3H, t), 1.15 (3H, t)[M + H]⁺ Example 41 7.40-7.30 (1H, m), 512

7.05 (1H,d), 7.00-6.90 (2H, m), 6.60-6.40 (1H, br s), 5.15-5.05 (1H, m),4.65-4.40 (3H, m), 3.80-3.60 (5H, m), 3.50-3.30 (2H, m), 2.75-2.60 (2H,m), 2.60-2.40 (2H, m), 2.40-2.20 (4H, m), 2.20-2.05 (2H, m), 2.05-1.90(2H, m), 1.80-1.50 (4H, m), 1.20 (3H, t) [M + H]⁺ Example 42 7.35-7.30(1H, m), 526

7.05 (1H, d), 7.00-6.90 (2H, m), 6.55-6.35 (1H, br s), 5.15-5.05 (1H, m)4.60-4.35 (3H, m), 3.80-3.60 (5H, m), 3.45-3.30 (2H, m), 2.75-2.60 (2H,m), 2.60-2.20 (8H, m), 2.20-2.05 (2H, m), 2.05-1.85 (2H, m), 1.75-1.45(4H, m), 1.25-1.10 (6H, m) [M + H]⁺ Example 43 7.35-7.30 (1H, m), 524

7.05 (1 H, d), 7.05-6.90 (2H, m), 6.90-6.60 (1H, br s), 5.20-5.10 (1H,m), 4.60-4.35 (3H, m), 3.80-3.60 (5H, m), 3.50-3.30 (2H, m), 2.75-2.60(2H, m), 2.60-2.20 (7H, m), 2.20-1.90 (4H, m), 1.75-1.50 (4H, m),1.45-1.30 (1H, m), 1.05-0.90 (2H, m), 0.85-0.70 (2H, m) [M + H]⁺

Example 44 Methyl1-endo-{8-[(3S)-3-(acetamido)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatemonohydrate

[0320]

[0321] Sodium triacetoxyborohydride (11.0 g, 51.9 mmol) was addedportionwise to a solution ofN-[(1S)-1-(3-fluorophenyl)-3-oxopropyl]acetamide (Preparation 43) (11.32g, 54.1 mmol) and methyl1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 48) (13.73 g, 45.1 mmol) in dichloromethane (150 ml) andthe mixture stirred for one hour at room temperature. The solution wasthen washed with water (100 ml), brine (50 ml) and dried (MgSO4).Solvent was evaporated under reduced pressure and the resulting whitesolid dissolved in ethyl acetate (100 ml). Slight cooling inducedcrystallisation which was allowed to complete at room temperatureovernight. The resulting white solid was filtered off and recrystalisedfrom acetone (4 ml/g) to give the title compound as a white crystallinesolid (15 g).

[0322] Found C, 62.80; H, 7.48; N, 13.55%; C27H37FN5O3.H2O requires C,62.89; H, 7.43; N, 13.58%

[0323] 1H NMR (400 MHz, CDCl3): δ: 7.30-7.25 (1H, m), 7.10-6.90 (3H, m),6.80-6.50 (1H, m), 5.20-5.10 (1H, q), 4.65-4.38 (3H, m), 3.80-3.60 (5H,m), 3.50-3.30 (2H, m), 2.80-1.90 (16H, m), 1.70-1.40 (4H, m) ppm.

[0324] LRMS (electrospray): m/z [M+H]⁺ 498.

[0325] The compound of Example 44 exhibits a weight loss of 3.58%between 33° C. and 172° C. under Thermogravimetric Analysis (TGA).Evolved Gas Analysis (EGA) revealed this weight loss to be attributed tothe evolution of water. This water is retained upon drying at 30° C./0%RH using Dynamic Vapour Sorption (DVS). Thus, the compound of Example 44exists as a monohydrate (1.03 moles H₂O). TGA was determined using a TAInstruments Q50 from ambient to 300° C. at a heating rate of 20° C./minwith helium purge gas. EGA was carried out by mass spectroscopy using aPfeiffer Thermostar GSD 300T with helium carrier gas. DVS was carriedout using a SMS Ltd DVS-1.

Example 45 Methyl1-{endo-8-[(3S)-3-acetamido-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatemonohydrate

[0326]

[0327] The title compound from Preparation 54 (184.8 g, 0.406 mol) wasslurried in ethyl acetate (930 ml), saturated sodium carbonate solution(930 ml) and water (930 ml). To the resultant two-phase solution wasadded acetyl chloride (35 ml, 0.490 mol) over 30 minutes, resulting in a9° C. exotherm. A sample was taken and analysis by HPLC showed that thereaction was complete. Dichloromethane (1.5 L) was added and thetwo-phase solution separated. The organic layer was washed with water(560 ml). The organic layer was evaporated under reduced pressure to avolume of 370 ml ethyl acetate. To the resultant solution was addedethyl acetate saturated with water (530 ml). The mixture was stirred atambient temperature for 30 minutes. A white solid formed and wascollected by filtration and dried in an oven under reduced pressure at50° C. overnight, to give the title compound as a monohydrate, 142.7 g,59%.

[0328] LRMS (Electrospray): m/z=498.5 (MH⁺)

Example 46 Methyl1-{endo-8-[(3S)-3-acetamido-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate(R,R)-tartrate

[0329]

[0330] L-Tartaric acid (46.4 g, 0.31 mol) was slurried in propan-2-ol(700 ml). To the resultant solution was added the title compound ofExample 45 (140 g, 0.28 mol) as a slurry in propan-2-ol (700 ml) over1.5 hours. The mixture was heated to reflux for 30 minutes. The reactionwas cooled to ambient temperature, then to 5° C. over 1 hour. The slurrywas stirred at 5° C. for 1.5 hours. The solid was collected byfiltration and dried in an oven under reduced pressure at 50° C.overnight to yield the title compound as a white solid, 177.9 g, 98%.

[0331] LRMS (Electrospray): m/z=498.5 (MH⁺)

Examples 47-49

[0332] Examples 47-49, respectively the (D)-tartrate, succinate andfumarate salts of methyl1-{endo-8-[(3S)-3-acetamido-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate,were prepared in the manner described for Example 46, employing thecorresponding acid.

Preparation 1

[0333] 8-Benzyl-8-azabicyclo[3.2.1]octan-3-one

[0334] A solution of 2,5-dimethoxytetrahydrofuran (50 g, 378 mmol) inhydrochloric acid (0.025 N, 160 ml) was cooled to 0° C. for 16 hours.Benzylamine hydrochloride (65 g, 453 mmol), ketomalonic acid (55 g, 377mmol) and an aqueous solution of sodium acetate (300 ml, 0.69 M) wereadded and the reaction stirred at room temperature for one hour. Themixture was heated to 50° C. for further 90 minutes, then cooled in anice bath and basified to pH12 with 2N sodium hydroxide solution. Thelayers were separated and the aqueous phase extracted with ethyl acetate(3×300 ml). The combined organic extracts were washed with water, dried(MgSO₄), filtered and evaporated under reduced pressure. The residualbrown oil was distilled under reduced pressure (126°/3 mmHg) to affordthe title compound as an off-white solid (37.81 g).

[0335]¹H NMR (400 MHz, CDCl₃): δ: 1.64 (2H, m), 2.06-2.14 (2H, m), 2.18(1H, s), 2.23 (1H, s), 2.68 (1H, m), 2.72 (1H, m), 3.48 (2H, s), 3.73(2H, s), 7.20-7.29 (1H, m), 7.32 (2H, m), 7.42 (2H, d) ppm.

[0336] LRMS: m/z 216.3 (MH⁺).

Preparation 2

[0337] tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octan-8-carboxylate

[0338] A mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one(Preparation 1) (15.0 g, 69.7 mmol), di-tert-butyl dicarbonate (18.2 g,83.4 mmol) and 20% w/w palladium hydroxide on carbon (3.0 g) in ethylacetate (165 ml) was stirred for 4 hours at room temperature under anatmosphere of hydrogen at 269 kPa. The mixture was filtered throughArbocel® and the solvent removed under reduced pressure. The residue waspurified by column chromatography on silica gel using an elutiongradient of hexane:ether (100:0 to 50:50) to afford the title compoundas a colourless oil which crystallized on standing (1 6.2 g).

[0339]¹H NMR (400 MHz, CDCl₃): δ:1.48 (9H, s), 1.60-1.68 (2H, m),2.00-2.11 (2H, m), 2.26-2.34 (2H, m), 2.48-2.82 (2H, m), 4.35-4.58 (2H,m) ppm.

Preparation 3

[0340] tert-Butyl3-(benzylamino)-endo-8-azabicyclo[3.2.1]octane-8-carboxylate

[0341] A solution of tert-butyl3-oxo-8-azabicyclo[3.2.1]octan-8-carboxylate (Preparation 2) (10.0 g,44.4 mmol), benzylamine (4.85 ml, 49.7 mmol) and sodiumtriacetoxyborohydride (14.11 g, 66.6 mmol) was stirred for 16 hours atroom temperature in a mixture of glacial acetic acid:dichloromethane(1:9 v/v, 290 ml). The solvents were evaporated under reduced pressureand the residue dissolved in ethyl acetate (200 ml), then washed withsaturated aqueous sodium carbonate solution (50 ml) and water (50 ml).The organic solution was dried (MgSO₄), filtered and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using an eluent of dichloromethane:methanol:concentratedaqueous ammonia (98:2:0.25) to afford the title compound as a whitesolid (7.00 g).

[0342]¹H NMR (400 MHz, CDCl₃): δ: 1.42-1.48 (11H, m), 1.52-1.61 (2H, m),1.85-2.19 (5H, m), 2.95-3.03 (1H, m), 3.74 (2H, s), 4.03-4.23 (2H, m),7.20-7.26 (1H, m), 7.26-7.32 (4H, m) ppm.

Preparation 4

[0343] tert-Butyl 3-endo-amino-8-azabicyclo[3.2.1]octane-8-carboxylate

[0344] A mixture of tert-butyl3-(benzylamino)-endo-8-azabicyclo[3.2.1]octane-8-carboxylate(Preparation 3) (7.00 g, 22.1 mmol), ammonium formate (7.00 g, 111 mmol)and 20% w/w palladium hydroxide on carbon (0.70 g) in ethanol (200 ml)was heated to 50° C., until gas evolution ceased. The cooled mixture wasfiltered through Arbocel® and the filtrate evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol:concentratedaqueous ammonia (98:2:0.25 to 95:5:0.5) to afford the title compound asa colourless oil (4.70 g).

[0345] LRMS: m/z 227.2 (MH⁺).

Preparation 5

[0346] 3-Fluoropyridine-N-oxide.

[0347] 3-Fluoropyridine (20 g, 0.20 mol) was dissolved in glacial aceticacid (120 ml) and slowly heated to 85° C. under a nitrogen atmosphere.Concentrated sulfuric acid (1 ml) was then added, followed byportion-wise addition of 30 wt. % hydrogen peroxide (52 ml, 0.41 mol).The mixture was refluxed for 1 day. The solvent was evaporated underreduced pressure and the residue taken up in dichloromethane (400 ml).Potassium hydrogen carbonate (30 g) was added to the solution and themixture was stirred for one hour. The solution was filtered andevaporated under reduced pressure to afford the title compound as ayellow oil which solidified on standing (26 g).

[0348]¹H-NMR (400 MHz, CDCl₃): δ: 7.05 (1H, m), 7.22 (1H, m), 8.10 (1H,m), 8.20 (1H, m) ppm.

Preparation 6

[0349] 3-Fluoro-4-nitropyridine N-oxide

[0350] Concentrated H₂SO₄ (75 ml) was carefully added to3-fluoropyridine N-oxide (Preparation 5) (50 g, 0.44 mol), cooled atroom temperature by using a water bath. Fuming nitric acid (55 ml) wasdissolved in concentrated sulfuric acid (75 ml) and the colourlesssolution was added drop-wise to the substrate over 15 minutes at roomtemperature. The yellow mixture was heated for 1.5 hours at 90° C. Themixture was allowed to reach room temperature and slowly poured onto ice(900 g). The aqueous layer was extracted with dichloromethane (3×500 ml)and the solvent evaporated under reduced pressure to yield a yellowsolid. This was washed with pentane (200 ml). The residue was dissolvedin dichloromethane (50 ml). A yellow precipitate formed which wasfiltered off to yield the title compound (10 g).

[0351] H-NMR (400 MHz, d₆-DMSO): δ: 8.20 (2H, m), 8.90 (1H, m) ppm.

Preparation 7

[0352] tert-Butyl3-endo-[(4-nitro-1-oxido-3-pyridinyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate

[0353] tert-Butyl 3-amino-endo-8-azabicyclo[3.2.1]octane-8-carboxylate(Preparation 4) (19 g, 0.084 mol) and 3-fluoro-4-nitropyridine N-oxide(Preparation 6) (13 g, 0.084 mol) were dissolved in acetonitrile (750ml). Anhydrous potassium carbonate (13.6 g, 0.098 mol) was then added inone portion and then the mixture was heated to reflux and stirred for 16hours under a nitrogen atmosphere. The solvent was evaporated underreduced pressure and the residue taken up into ethyl acetate (750 ml),washed with water (100 ml), then brine (100 ml). The organic layer wasdried (MgSO₄) and the solvent removed by evaporated under reducedpressure. This residue was washed with diethyl ether (100 ml) andfiltered to afford the title compound as a yellow solid (16 g).

[0354]¹H-NMR (400 MHz, CDCl₃): δ: 1.42 (9H, s), 1.62 (3H, m), 1.8 (2H,d), 1.97 (2H, m), 2.10 (2H, m), 2.30 (2H, m), 3.80 (1H, m), 7.42 (1H,m), 7.80 (1H, m), 8.10 (1H, m), 8.60 (1H, m) ppm.

[0355] LRMS: m/z 387 (MH⁺).

Preparation 8

[0356]3-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-3H-imidazo[4,5-c]pyridine

[0357] tert-Butyl3-endo-[(4-nitro-1-oxido-3-pyridinyl)amino]-8-azabicyclo[3.2.1]-octane-8-carboxylate(Preparation 7) (15 g, 0.04 mol) was dissolved in glacial acetic acid(100 ml) at room temperature. Iron powder (8.0 g, 0.144 mol) was addedand the mixture heated to 130° C. for 4 hours. Acetic anhydride (100 ml)was added and the mixture heated to 140° C. for 3 days. The solvent wasremoved under reduced pressure, and water (200 ml) was added. Sodiumhydroxide pellets were added to the mixture until pH 10. The mixture wasextracted with dichloromethane (1000 ml) and the organic extract dried(Na₂SO₄). The solvent was evaporated under reduced pressure to affordthe title compound as a pale-yellow solid (7.4 g).

[0358]¹H-NMR (400 MHz, CDCl₃): δ: 1.90-2.10 (3H, m), 2.18 (3H, s),2.20-2.30 (3H, m), 2.50-2.70 (5H, m), 4.22 (1H, m), 4.40 (1H, m), 4.90(1H, m), 7.60 (1H, d), 8.40 (1H, d), 8.82 (1H, s) ppm.

[0359] LRMS: m/z 285 (MH⁺).

Preparation 9

[0360]3-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-3H-imidaz[4,5-c]pyridine

[0361]3-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-3H-imidazo[4,5-c]pyridine(Preparation 8) (2.69 g, 9.5 mmol) was dissolved in glacial acetic acid(50 ml) and hydrogenated at 400 kPa and 60° C. for 18 hours. The coolreaction mixture was filtered through a pad of Arbocel® and the filtrateevaporated under reduced pressure. The residue was dissolved in water(70 ml) and solvent evaporated under reduced pressure. The residue wasagain dissolved in water (70 ml) and the solution adjusted to pH10 bythe addition of 2N aqueous sodium hydroxide solution. The aqueoussolution was extracted with dichloromethane (4×100 ml), the combinedorganic extracts dried (Na₂SO₄) and solvent evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (90:10:1, byvolume, changing to 85:15:1). Product containing fractions wereevaporated to afford the title compound as a white foam (2.6 g).

[0362]¹H NMR (400 MHz, CDCl₃): δ: 4.85-4.80 (1H, m), 4.25-4.20 (1H, m),3.95 (2H, s), 3.90-3.80 (1H, m), 3.10 (2H, m), 2.70-2.45 (5H, m), 2.35(3H, s), 2.20-2.00 (5H, m), 1.80-1.60 (4H, m) ppm.

[0363] LRMS (electrospray): m/z [M+Na]⁺ 311, [M+H]⁺ 289.

Preparation 10

[0364]3-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0365] Acetic acid (0.9 ml, 15.6 mmol) was added to a stirred solutionof3-endo-(8-acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridine(Preparation 9) (2.6 g, 9 mmol) and benzaldehyde (1.2 ml, 11.8 mmol)dissolved in dichloromethane (50 ml) under nitrogen at room temperature.Sodium triacetoxyborohydride (3.1 g, 14.6 mmol) was then added and thereaction was held at room temperature for 18 hours. The reaction mixturewas partitioned between saturated aqueous sodium hydrogencarbonatesolution (50 ml) and dichloromethane (50 ml). The organic phase wasremoved and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.8). Product containing fractions wereevaporated to afford the title compound as a white solid (1.6 g).

[0366]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.25 (5H, m), 4.75 (1H, m), 4.15(1H, m), 3.85 (1H, m), 3.70 (2H, s), 3.45 (2H, s), 2.85 (2H, m), 2.65(2H, m), 2.50-2.35 (2H, m), 2.30 (3H, s), 2.10 (3H, s), 2.05-1.90 (2H,m), 1.60-1.35 (4H, m) ppm.

[0367] LRMS (electrospray): m/z [M+Na]⁺ 401, [M+H]⁺ 379.

Preparation 11

[0368]3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0369]3-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine(Preparation 10) (2.6 g, 7 mmol) was dissolved in 6N aqueoushydrochloric acid (25 ml) and heated under reflux for 42 hours. Thecooled reaction mixture was diluted with water (25 ml) and washed withdiethyl ether (50 ml). The aqueous layer was adjusted to pH10 by theaddition of 2N aqueous sodium hydroxide solution and extracted withdichloromethane (3×100 ml). The combined organic extracts were dried(Na₂SO₄) and solvent evaporated under reduced pressure to afford thetitle compound as a colourless gum, (2.05 g).

[0370]¹H-NMR (400 MHz, CDCl₃): δ 7.40-7.20 (5H, m), 4.25 (1H, m), 3.70(2H, s), 3.60 (2H, m), 3.45 (2H, s), 2.85 (2H, m), 2.65 (2H, m),2.40-2.30 (5H, m), 1.70 (2H, m), 1.40-1.30 (4H, m) ppm.

[0371] LRMS (electrospray): m/z [M+Na]⁺ 359, [M+H]⁺ 337.

Preparation 12

[0372] tert-Butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate

[0373] Acetic acid (0.6 ml, 10.4 mmol) was added to a stirred solutionof3-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine(Preparation 11) (2.0 g, 6 mmol) and tert-butyl(1S)-3-oxo-1-phenylpropylcarbamate (WO0039125) (1.7 g, 6.8 mmol)dissolved in dichloromethane (40 ml) under nitrogen at room temperature.Sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was then added and thereaction was held at room temperature for 18 hours. The reaction mixturewas partitioned between saturated aqueous sodium hydrogencarbonatesolution (50 ml) and dichloromethane (50 ml). The organic phase wasremoved and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (96:4:0.4, byvolume, changing to 94:6:0.6). Product containing fractions wereevaporated to afford the title compound as a white foam (2.53 g).

[0374]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (10H, m), 5.90 (1H, br s),4.80 (1H, br s), 4.40 (1H, m), 3.70 (2H, s), 3.50 (2H, s), 3.30 (1H, m),3.20 (1H, m), 2.85 (2H, m), 2.65 (2H, m), 2.45-2.30 (5H, m), 2.20 (2H,m), 2.00-1.70 (4H, m), 1.45-1.20 (13H, m) ppm.

[0375] LRMS (electrospray): m/z [M+Na]⁺ 592, [M+H]⁺ 570.

Preparation 13

[0376](1S)-3-[3-endo-(5-Benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine

[0377] A solution of tert-butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 12) (2.4 g, 4.2 mmol) in 2.25 N HCl solution in methanol(20 ml) was stirred under nitrogen at room temperature for 18 hours.Solvent was evaporated under reduced pressure and the residuepartitioned between ethyl acetate (100 ml) and 1N aqueous sodiumhydroxide solution (50 ml). The organic layer was washed with water (50ml), dried (Na₂SO₄) and solvent evaporated under reduced pressure togive the title compound as a colourless gum (1.8 g).

[0378]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (10H, m), 4.30 (1H, m), 4.00(1H, m), 3.70 (2H, s), 3.50 (2H, s), 3.35 (2H, m), 2.85 (2H, m), 2.65(2H, m), 2.40-2.30 (5H, m), 2.20 (2H, m), 1.90 (2H, m), 1.80 (2H, m),1.65 (2H, br s), 1.35-1.15 (4H, m) ppm.

[0379] LRMS (electrospray): m/z [M+H]⁺ 470.

Preparation 14

[0380](1S)-3-[3-endo-(2,5-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine

[0381] A solution of the title compound of Example 5 (0.26 g, 0.6 mmol)was dissolved in 6N aqueous hydrochloric acid (4 ml) and heated underreflux for 42 hours. The cooled reaction mixture was adjusted to pH10 bythe addition of 2N aqueous sodium hydroxide solution and extracted withdichloromethane (3×30 ml). The combined organic phases were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica geleluting with a solvent gradient of dichloromethane:methanol:concentratedaqueous ammonia (90:10:0.5, by volume, changing to 90:10:1). Productcontaining fractions were evaporated to afford the title compound as acolourless gum (0.18 g).

[0382]¹H-NMR (400 MHz, CDCl₃): δ 7.40-7.20 (5H, m), 4.25 (1H, m), 3.70(2H, s), 3.60 (2H, m), 3.45 (2H, s), 2.85 (2H, m), 2.65 (2H, m),2.40-2.30 (5H, m), 1.70 (2H, m), 1.40-1.30 (4H, m) ppm.

[0383] LRMS (electrospray): m/z [M+Na]⁺ 359, [M+H]⁺ 337.

Preparation 15

[0384] tert-Butyl (1S)-1-(3-fluorophenyl)-3-oxopropylcarbamate

[0385] Diisobutylaluminium hydride (1 M in dichloromethane, 39 ml, 39mmol) was cooled to −78° C. and added dropwise to a solution of methyl(3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propanoate (WO0039125) (5.4 g, 18.2 mmol) in dichloromethane (100 ml) at −78° C. Thereaction was stirred for 30 minutes at −78° C., then methanol (50 ml,pre-cooled to −78° C.) was added. The reaction was stirred for 30minutes, then 2 N hydrochloric acid (250 ml) added. The bi-phasicmixture was allowed to warm up to room temperature, the layers wereseparated, and the organic layer was dried (MgSO₄), filtered andevaporated under reduced pressure to afford the title compound as aclear, colourless oil, 4.8 g.

[0386]¹H-NMR (400 MHz, CDCl₃): δ: 1.40 (9H, bs), 2.92 (2H, m), 5.14 (2H,m), 6.90-7.02 (2H, m), 7.03 (1H, d), 7.30 (1H, m), 9.76 (1H, s) ppm.

[0387] LRMS: m/z 268.1 (MH⁺).

Preparation 16

[0388] tert-Butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate

[0389] Acetic acid (0.3 ml, 5.2 mmol) was added to a stirred solution of3-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine(Preparation 11) (1.74 g, 5.2 mmol) and tert-butyl(1S)-1-(3-fluorophenyl)-3-oxopropylcarbamate (Preparation 15) (1.52 g,5.7 mmol) dissolved in dichloromethane (25 ml) under nitrogen at roomtemperature. Sodium triacetoxyborohydride (1.31 g, 6.2 mmol) was thenadded and the reaction was held at room temperature for two hours. Thereaction mixture was partitioned between saturated aqueous sodiumhydrogencarbonate solution (50 ml) and dichloromethane (50 ml). Theorganic phase was removed and the aqueous phase was washed withdichloromethane (50 ml). The combined organic phases were dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (100:0:0.5, by volume, changing to 97:3:0.5). Product containingfractions were evaporated to afford the title compound as a white foam(1.8 g).

[0390]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (6H, m), 7.05-6.85 (3H, m),6.10-5.80 (1H, br s), 4.85-4.65 (1H, m), 4.40-4.25 (1H, m), 3.70 (2H,s), 3.45 (2H, s), 3.30-3.10 (2H, m), 2.90-2.80 (2H, m), 2.70-2.60 (2H,m), 2.50-2.30 (5H, m), 2.25-2.15 (2H, m), 2.10-1.65 (5H, m), 1.60-1.10(12H, m) ppm.

[0391] LRMS (electrospray): m/z [M+H]⁺ 588.

Preparation 17

[0392] tert-Butyl(1S)-1-(3-fluorophenyl)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]propylcarbamate

[0393] A mixture of tert-butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate(Preparation 16) (2.00 g, 3.4 mmol), ammonium formate (1.07 g, 17 mmol)and 10% w/w palladium on carbon (0.15 g) in ethanol (30 ml) was heatedto 60° C. After one hour additional ammonium formate (1.07 g, 17 mmol)was added and heating continued at 60 ° C. This process was repeatedafter a further hour. One hour after the second addition heating wasremoved and the cooled reaction mixture filtered through Arbocel® andthe filtrate evaporated under reduced pressure. The residue waspartitioned between dichloromethane (100 ml) and saturated aqueoussodium hydrogencarbonate solution (50 ml), the organic phase separatedand washed with water (30 ml). The organic layer was dried (MgSO₄) andsolvent evaporated under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(90:10:1). Product containing fractions were evaporated to afford thetitle compound as a white foam (1.45 g).

[0394]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.20 (1H, m), 7.10-6.85 (3H, m),5.85-5.65 (1H, m), 4.90-4.65 (1H, m), 4.50-4.35 (1H, m), 3.95 (2H, s),3.40-3.20 (2H, m), 3.10 (2H, t), 2.65-2.20 (10H, m), 2.15-1.65 (4H, m),1.60-1.20 (13H, m) ppm.

[0395] LRMS (electrospray): m/z [M+H]⁺ 498.

Preparation 18

[0396] tert-Butyl(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate

[0397] Acetyl chloride (0.13 g, 1.65 mmol) was added to a solution oftert-butyl(1S)-1-(3-fluorophenyl)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]propylcarbamate(Preparation 17) (0.75 g, 1.5 mmol) in dichloromethane (5 ml) at 0° C.After 30 minutes the reaction mixture was diluted with dichloromethane(10 ml) and washed with saturated aqueous sodium hydrogencarbonatesolution (10 ml). The organic layer was separated and the aqueous phasewashed with dichloromethane (2×5 ml). The combined organic extracts weredried (MgSO₄) and solvent evaporated under reduced pressure to affordthe title compound as a white foam (0.8 g).

[0398]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.20 (1H, m), 7.05-6.85 (3H, m),5.90-5.70 (1H, m), 4.85-4.35 (4H, m), 3.65-3.60 (2H, t), 3.40-3.20 (2H,m), 2.70-1.00 (29H, m) ppm.

[0399] LRMS (electrospray): m/z [M+H]⁺ 540.

Preparation 19

[0400] Methyl3-endo-{8-[(3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0401] Methyl chloroformate (0.156 g, 1.65 mmol) was added to a solutionof tert-butyl(1S)-1-(3-fluorophenyl)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]propylcarbamate(Preparation 17) (0.75 g, 1.5 mmol) in dichloromethane (5 ml) at 0° C.After 30 minutes the reaction mixture was diluted with dichloromethane(10 ml) and washed with saturated aqueous sodium hydrogencarbonatesolution (10 ml). The organic layer was separated and the aqueous phasewashed with dichloromethane (2×5 ml). The combined organic extracts weredried (MgSO₄) and solvent evaporated under reduced pressure to affordthe title compound as a white foam (0.77 g).

[0402]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.20 (1H, m), 7.05-6.85 (3H, m),5.90-5.70 (1H, m), 4.90-4.70 (1H, m), 4.60-4.40 (3H, m), 3.75-3.60 (5H,m), 3.40-3.25 (2H, m), 2.65-2.38 (7H, m), 2.25-2.20 (2H, m), 2.15-1.20(17H, m) ppm.

[0403] LRMS (electrospray): m/z [M+H]⁺ 556.

Preparation 20

[0404](1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylamine

[0405] Hydrogen chloride gas was bubbled through a solution oftert-butyl(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate(Preparation 18) (0.77 g, 1.43 mmol) in dichloromethane (10 ml) andmethanol (3 ml) at 0° C. until the solution was saturated. The reactionmixture was then allowed to warm to room temperature and after 20minutes solvent was evaporated under reduced pressure. The residue waspartitioned between dichloromethane (30 ml) and saturated aqueous sodiumhydrogencarbonate solution (20 ml). The organic layer was separated andthe aqueous phase extracted with dichloromethane (2×15 ml). The combinedorganic extracts were dried (MgSO₄) and solvent evaporated under reducedpressure to afford the title compound as a white foam (0.565 g).

[0406]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.20 (1H, m), 7.10-6.90 (3H, m),4.60 (2H, s), 4.45-4.30 (1H, m), 4.05 (1H, t), 3.62 (2H, t), 3.40-3.25(2H, m), 2.70-1.95 (14H, m), 1.85-1.40 (8H, m) ppm.

[0407] LRMS (electrospray): m/z [M+H]⁺ 440.

Preparation 21

[0408] Methyl3-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0409] Hydrogen chloride gas was bubbled through a solution of methyl3-endo-{8-[(3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 19) (0.75 g, 1.35 mmol) in dichloromethane (10 ml) andmethanol (3 ml) at 0° C. until the solution was saturated. The reactionmixture was then allowed to warm to room temperature and after 20minutes solvent was evaporated under reduced pressure. The residue waspartitioned between dichloromethane (30 ml) and saturated aqueous sodiumhydrogencarbonate solution (20 ml). The organic layer was separated andthe aqueous phase extracted with dichloromethane (2×15 ml). The combinedorganic extracts were dried (MgSO₄) and solvent evaporated under reducedpressure to afford the title compound as a white foam (0.566 g).

[0410]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.20 (1H, m), 7.10-7.00 (2H, m),6.95-6.85 (1H, t), 4.60-4.30 (3H, m), 4.05 (1H, t), 3.75-3.60 (5H, m),3.40-3.25 (2H, m), 2.65-2.55 (2H, m), 2.50-2.35 (5H, m), 2.30-2.15 (2H,m), 2.10-1.95 (2H, m), 1.85-1.35 (8H, m) ppm.

[0411] LRMS (electrospray): m/z [M+H]⁺ 456.

Preparation 22

[0412] tert-Butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate

[0413] A mixture of tert-butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 12) (5.65 g, 9.93 mmol), ammonium formate (3.7 g, 58.7mmol) and 20% w/w palladium hydroxide on carbon (0.50 g) in ethanol (100ml) was heated to 85° C. After one hour additional ammonium formate (2.0g, 17 mmol) was added and heating continued at 60° C. for a furtherhour. The cooled reaction mixture was then filtered through Arbocel® andthe filtrate evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(94:6:0.6, by volume, changing to 92:8:0.8). Product containingfractions were evaporated to afford the title compound as a white foam(4.95 g).

[0414]¹H NMR (400 MHz, CDCl₃): δ: 7.35-7.20 (5H, m), 5.70 (1H, m), 4.80(1H, m), 4.45 (1H, m), 3.90 (2H, s), 3.40-3.25 (2H, m), 3.10 (2H, t),2.60 (2H, m), 2.55-2.40 (5H, m), 2.20 (2H, t), 2.10-1.75 (4H, m),1.55-1.20 (14H, m) ppm.

[0415] LRMS (electrospray): m/z [M+H]⁺ 480.

Preparation 23

[0416] tert-Butyl(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylcarbamate

[0417] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54g, 2.82 mmol) was added to a solution of 3,3,3-trifluoropropanoic acid(0.29 g, 2.26 mmol), tert-butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 22) (0.96 g, 2.0 mmol), triethylamine (0.6 ml, 4.31 mmol)and 1-hydroxybenzotriazole (0.43 g, 2.81 mmol) dissolved indichloromethane (50 ml) under nitrogen at room temperature. The reactionwas stirred at room temperature for 18 hours, and then washed withsaturated aqueous sodium hydrogencarbonate solution (30 ml). The organicphase was removed and the aqueous layer extracted with dichloromethane(2×30 ml). The combined dichloromethane extracts were dried (MgSO₄) andthe solvent was removed under reduced pressure. The residue was purifiedby flash column chromatography on silica gel eluting with a solventmixture of dichloromethane:methanol:concentrated aqueous ammonia(94:6:0.6, by volume). Product containing fractions were evaporated toafford the title compound as a white foam (1.09 g).

[0418]¹H NMR (400 MHz, CDCl₃): δ: 7.35-7.20 (5H, m), 5.65 (1H, m), 4.80(1H, m), 4.70 (2H, s), 4.60-4.45 (2H, m), 3.70 (2H, m), 3.40-3.25 (4H,m), 2.70-2.60 (2H, m), 2.55-2.40 (5H, m), 2.25 (2H, m), 2.10-1.70 (4H,m), 1.55-1.20 (12H, m) ppm.

[0419] LRMS (electrospray): m/z [M+H]⁺ 590.

Preparation 24

[0420](1S)-3-{3-endo-[2-Methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylamine

[0421] Hydrogen chloride gas was bubbled through a solution oftert-butyl(1S)-3-{3-endo-[2-methyl-5-(3,3,3-trifluoropropanoyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropylcarbamate(Preparation 23) (1.05 g, 1.78 mmol) in dichloromethane (20 ml) andmethanol (3 ml) at 0° C. until the solution was saturated. The reactionmixture was then allowed to warm to room temperature and after one hourwashed with 2N aqueous sodium hydroxide solution (2×20 ml). The organiclayer was separated, dried (MgSO₄) and solvent evaporated under reducedpressure to afford the title compound as a white foam (0.80 g).

[0422]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.30 (5H, m), 4.70 (2H, m), 4.40(1H, m), 4.05 (1H, t), 3.65 (2H, m), 3.40-3.25 (4H, m), 2.70-2.60 (2H,m), 2.50-2.30 (5H, m), 2.25 (2H, m), 2.05 (2H, m), 1.85-1.40 (8H, m)ppm.

[0423] LRMS (electrospray): m/z [M+H]⁺ 490.

Preparation 25

[0424] Methyl3-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0425] Methyl chloroformate (0.18 ml, 2.32 mmol) was added to a solutionof tert-butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 22) (0.96 g, 2.0 mmol) and triethylamine (0.36 ml, 2.59mmol) in dichloromethane (20 ml) under nitrogen at room temperature. Thereaction was stirred at room temperature for 1.5 hours and then washedwith saturated aqueous sodium hydrogencarbonate solution (20 ml). Theorganic phase was removed and the aqueous layer extracted with moredichloromethane (2×20 ml). The combined dichloromethane extracts weredried (MgSO₄) and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography on silica geleluting with a solvent mixture of ethyl acetate:diethylamine (99:1, byvolume, changing to 98:2 then 97:3). Product containing fractions wereevaporated to afford the title compound as a white foam (0.96 g).

[0426]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.25 (5H, m), 5.65 (1H, m), 4.80(1H, m), 4.60-4.40 (3H, m), 3.75-3.65 (5H, m), 3.40-3.25 (2H, m), 2.65(2H, m), 2.55-2.40 (5H, m), 2.25 (2H, m), 2.15-2.05 (2H, m), 2.00-1.8(2H, m), 1.65-1.30 (13H, m) ppm.

[0427] LRMS (electrospray): m/z [M+H]⁺ 538.

Preparation 26

[0428] Methyl3-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate

[0429] Hydrogen chloride gas was bubbled through a solution of methyl3-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 25) (0.95 g, 1.77 mmol) in dichloromethane (20 ml) andmethanol (1 ml) at 0° C. until the solution was saturated. The reactionmixture was then allowed to warm to room temperature and after one hourwashed with 2N aqueous sodium hydroxide solution (2×20 ml). The organiclayer was separated, dried (MgSO₄) and solvent evaporated under reducedpressure to afford the title compound as a white foam (0.75 g).

[0430]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.30 (5H, m), 4.55 (2H, br s),4.40 (1H, m), 4.05 (1H, t), 3.75-3.65 (5H, m), 3.35 (2H, m), 2.60 (2H,m), 2.45 (2H, m), 2.35 (3H, s), 2.25 (2H, m), 2.10 (2H, m), 1.80 (2H,m), 1.65-1.40 (6H, m) ppm.

[0431] LRMS (electrospray): m/z [M+H]⁺ 439.

Preparation 27

[0432] tert-Butyl(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate

[0433] Acetyl chloride (0.09 ml, 1.26 mmol) was added to a solution oftert-butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 22) (0.5 g, 1.09 mmol) and triethylamine (0.19 ml, 1.36mmol) in dichloromethane (5 ml) under nitrogen at room temperature. Thereaction was stirred at room temperature for 18 hours and then solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (94:6:0.6, byvolume, changing to 92:8:0.8 then 90:10:0.6). Product containingfractions were evaporated to afford the title compound as a white foam(0.51 g).

[0434]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (5H, m), 5.65 (1H, m), 4.80(1H, m), 4.65 (2H, s), 4.55-4.40 (2H, m), 3.85 (1H, m), 3.65 (2H, m),3.40-3.25 (2H, m), 2.70 (2H, m), 2.55-2.40 (5H, m), 2.25 (2H, m), 2.15(3H, s), 2.10-2.00 (2H, m), 1.95-1.75 (2H, m), 1.65-1.30 (13H, m) ppm.

[0435] LRMS (electrospray): m/z [M+H]⁺ 522.

Preparation 28

[0436](1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine

[0437] Hydrogen chloride gas was bubbled through a solution oftert-butyl(1S)-3-[3-endo-(5-acetyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 27) (0.50 g, 0.96 mmol) in dichloromethane (5 ml) andmethanol (0.5 ml) at 0° C. until the solution was saturated. Thereaction mixture was then allowed to warm to room temperature and afterone hour washed with 2N aqueous sodium hydroxide solution (2×5 ml). Theorganic layer was separated, dried (MgSO₄) and solvent evaporated underreduced pressure to afford the title compound as a white foam (0.265 g).

[0438]¹H NMR (400 MHz, CDCl₃): δ: 7.35-7.20 (5H, m), 4.60 (2H, br s),4.45-4.30 (1H, m), 4.00 (1H, t), 3.60 (2H, m), 3.40-3.30 (2H, m),2.50-2.30 (2H, m), 2.30-2.15 (2H, m), 2.13 (3H, s), 2.10-2.00 (2H, m),1.80 (2H, m), 1.70-1.40 (6H, m) ppm.

[0439] LRMS (electrospray): m/z [M+H]⁺ 422.

Preparation 29

[0440] tert-Butyl3-endo-[(3-nitro-4-pyridinyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate

[0441] tert-Butyl 3-amino-endo-8-azabicyclo[3.2.1]octane-8-carboxylate(Preparation 4) (3.0 g, 13.2 mmol), 4-ethoxy-3-nitropyridinehydrochloride (2.7 g, 13.2 mmol) and N-ethyl-N,N-diisopropylamine (1.89g, 14.6 mmol) were dissolved in 1-methyl-2-pyrrolidinone (5 ml) andheated at 120° C. for 18 hours. The cooled reaction mixture was dilutedwith ethyl acetate (150 ml) and washed with water (3×50 ml), saturatedaqueous sodium hydrogen carbonate solution (50 ml) and brine (30 ml).The organic layer was dried (MgSO₄) and the solvent removed byevaporation under reduced pressure. This residue was triturated withdiethyl ether and filtered to afford the title compound as a yellowsolid (1.5 g).

[0442]¹H-NMR (300 MHz, CDCl₃): δ: 1.40-2.50 (17H, m), 3.90-4.05 (1H, q),4.15-4.50 (2H, m), 6.60 (1H, d), 8.35 (1H, d), 8.75-9.00 (1H, d), 9.25(1H, s) ppm.

[0443] LRMS: m/z 349 (MH⁺).

Preparation 30

[0444]1-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-imidazo[4,5-c]pyridine

[0445] tert-Butyl3-endo-[(3-nitro-4-pyridinyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate(Preparation 29) (4.40 g, 12.6 mmol) and iron powder (2.11 g, 37.8 mmol)were dissolved in glacial acetic acid (50 ml) and the mixture heated to60° C. for two hours. Acetic anhydride (8 ml) was then added and themixture heated to 140° C. for 18 hours. The cooled reaction mixture wasfiltered through a pad of Arbocel® and solvent was removed under reducedpressure The residue was partitioned between dichloromethane (200 ml)and water (200 ml) and the mixture adjusted to pH 9 with 2 N aqueoussodium hydroxide solution. The mixture was again filtered through a padof Arbocel® and the organic phase separated. The aqueous layer wasextracted with dichloromethane (100 ml) and the combined organicextracts dried (MgSO₄). Solvent was evaporated under reduced pressureand the residue triturated with ethyl acetate, filtered and dried(MgSO₄) to give the title compound as a white solid (3.27 g).

[0446]¹H-NMR (400 MHz, CDCl₃): δ: 1.80-2.35 (9H, m), 2.45-2.70 (5H, m),4.10-4.25 (1H, m), 4.35 (1H, t), 4.90 (1H, t), 7.22 (1H, d), 8.35 (1H,d), 8.95 (1H, s) ppm.

[0447] LRMS: m/z 285 (MH⁺).

Preparation 31

[0448]1-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4.5-c]pyridine

[0449] Benzyl bromide (1.78 g, 10.4 mmol) was added to a solution of1-endo-(8-acetyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-imidazo[4,5-c]pyridine(Preparation 30) (2.47 g, 8.7 mmol) in ethanol (20 ml) and the mixturestirred at room temperature for 48 hours. The reaction mixture was thencooled to −70° C. and sodium borohydride (0.33 g, 8.7 mmol) addedportionwise over ten minutes. After one hour at −70° C. the reactionmixture was allowed to warm to −40° C. then re-cooled to −70° C. andfurther sodium borohydride (0.33 g, 8.7 mmol) added. After an additionalhour at −70° C. water (10 ml) was added and the reaction mixture allowedto warm to room temperature. The ethanol was evaporated under reducedpressure and the aqueous residue extracted with dichloromethane (3×25ml). The combined organic extracts were dried (MgSO₄) and solventevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofethyl acetate:methanol:diethylamine (100:0:2, by volume, changing to98:2:2 then 95:5:2). Product containing fractions were evaporated toafford the title compound as a white foam (2.23 g).

[0450]¹H-NMR (400 MHz, CDCl₃): δ: 1.60-1.85 (4H, m), 1.95-2.20 (5H, m),2.30 (3H, s), 2.35-2.75 (6H, m), 3.45 (2H, s), 3.65 (2H, s), 3.90 (1H,m), 4.20 (1H, t), 4.80 (1H, t), 7.15-7.35 (5H, m) ppm.

[0451] LRMS: m/z 379 (MH⁺).

Preparation 32

[0452]1-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine

[0453]1-endo-(8-Acetyl-8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine(Preparation 31) (2.23 g, 5.89 mmol) was dissolved in 6N aqueoushydrochloric acid (30 ml) and heated under reflux for 18 hours. Thecooled reaction mixture was adjusted to pH10 by the addition of 2Naqueous sodium hydroxide solution and extracted with dichloromethane(2×50 ml). The combined organic extracts were dried (MgSO₄) and solventevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:diethylamine (100:0:0.5, by volume, changing to93:7:1). Product containing fractions were evaporated to afford thetitle compound as a white foam (1.47 g).

[0454]¹H-NMR (400 MHz, CDCl₃): δ: 1.40-1.85 (7H, m), 2.30-2.40 (5H, m),2.60-2.75 (4H, m), 3.45 (2H, s), 3.60-3.70 (4H, m), 4.30 (1H, m),7.20-7.35 (5H, m) ppm.

[0455] LRMS (electrospray): m/z [M+H]⁺ 337.

Preparation 33

[0456] tert-Butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate

[0457] Acetic acid (0.14 g, 2.37 mmol) was added to a stirred solutionof1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine(Preparation 32) (0.8 g, 2.37 mmol) and tert-butyl(1S)-3-oxo-1-phenylpropylcarbamate (WO0039125) (0.711 g, 2.85 mmol)dissolved in dichloromethane (12 ml) under nitrogen at room temperature.Sodium triacetoxyborohydride (0.60 g, 2.85 mmol) was then added and thereaction was held at room temperature for 18 hours. The reaction mixturewas partitioned between saturated aqueous sodium hydrogencarbonatesolution (50 ml) and dichloromethane (50 ml). The organic phase wasremoved and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (99:1:0.1, byvolume, changing to 90:10:1). Product containing fractions wereevaporated to afford the title compound as a white foam (1.17 g).

[0458]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (10H, m), 5.80 (1H, m), 4.80(1H, m), 4.40 (1H, m), 3.65 (2H, s), 3.50 (2H, m), 3.40-3.20 (2H, m),2.70-2.60 (4H, m), 2.55-2.35 (5H, m), 2.20 (2H, t), 2.10-1.10 (17H, m)ppm.

[0459] LRMS (electrospray): m/z [M+H]⁺ 570.

Preparation 34

[0460] tert-Butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate

[0461] A mixture of tert-butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 33) (1.15 g, 2.02 mmol), ammonium formate (0.63 g, 10.1mmol) and 20% w/w palladium hydroxide on carbon (0.15 g) in ethanol (25ml) was heated to 60° C. After one hour additional ammonium formate(0.63 g, 10.1 mmol) was added and heating continued at 60° C. for afurther hour. This process was repeated three times. The cooled reactionmixture was then filtered through Arbocel® and the filtrate evaporatedunder reduced pressure. The residue was partitioned betweendichloromethane (100 ml) and saturated aqueous sodium hydrogencarbonatesolution (50 ml), the organic phase separated and washed with water (30ml). The organic layer was dried (MgSO₄) and solvent evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:concentrated aqueous ammonia (99:1:0.1 changingto 93:7:1). Product containing fractions were evaporated to afford thetitle compound as a white foam (0.85 g).

[0462]¹H NMR (400 MHz, CDCl₃): δ: 7.35-7.15 (5H, m), 5.75 (1H, m),4.90-4.70 (1H, m), 4.45 (1H, m), 3.80 (2H, s), 3.40-3.20 (2H, m),3.15-3.00 (2H, m), 2.70-2.60 (2H, m), 2.50-2.35 (5H, m), 2.30-1.70 (7H,m), 1.65-1.10 (13H, m) ppm.

[0463] LRMS (electrospray): m/z [M+H]⁺ 480.

Preparation 35

[0464] Methyl1-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0465] Methyl chloroformate (0.078 ml, 1.02 mmol) was added to asolution of tert-butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate(Preparation 34) (0.44 g, 0.92 mmol) in dichloromethane (4 ml) undernitrogen at room temperature. The reaction was stirred at roomtemperature for 1.5 hours and then washed with saturated aqueous sodiumhydrogencarbonate solution (10 ml). The organic phase was removed andthe aqueous layer extracted with more dichloromethane (2×10 ml). Thecombined dichloromethane extracts were dried (MgSO₄) and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with a solvent mixture ofdichloromethane:methanol:concentrated aqueous ammonia (99:1:0.1 changingto 93:7:1). Product containing fractions were evaporated to afford thetitle compound as a white foam (0.51 g).

[0466]¹H NMR (400 MHz, CDCl₃): δ: 7.30-7.20 (5H, m), 5.65 (1H, m),4.90-4.70 (1H, m), 4.50-4.30 (3H, m), 3.80-3.60 (5H, m), 3.40-3.20 (2H,m), 2.65 (2H, m), 2.50-2.35 (5H, m), 2.25 (2H, m), 2.15-1.10 (17H, m)ppm.

[0467] LRMS (electrospray): m/z [M+H]⁺ 538.

Preparation 36

[0468] Methyl1-endo-{8-[(3S)-3-amino-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride

[0469] Hydrogen chloride gas was bubbled through a solution of methyl1-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 35) (0.5 g, 0.93 mmol) in dichloromethane (10 ml) andmethanol (1 ml) at 0° C. until the solution was saturated. The reactionmixture was then allowed to warm to room temperature and stirred for onehour. Solvent was evaporated under reduced pressure and the residuesuspended in dichloromethane (10 ml). This process was repeated threetimes to give the title compound as a white solid (0.512 g).

[0470]¹H NMR (400 MHz, d₆-DMSO): δ: 11.30-11.10 (1H, br s), 8.90-8.60(3H, br s), 7.60 (2H, m), 7.50-7.35 (3H, m), 5.80-5.60 (1H, m),4.50-4.35 (3H, m), 4.20-4.00 (2H, m), 3.80-3.30 (9H, m), 3.25-3.10 (1H,m), 3.00-1.90 (13H, m) ppm.

[0471] LRMS (electrospray): m/z [M+H]⁺ 438.

Preparation 37

[0472] tert-Butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate

[0473] Acetic acid (0.39 g, 6.4 mmol) was added to a stirred solution of1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine(Preparation 32) (2.16 g, 6.4 mmol) and tert-butyl(1S)-1-(3-fluorophenyl)-3-oxopropylcarbamate (Preparation 15) (2.06 g,7.7 mmol) dissolved in dichloromethane (25 ml) under nitrogen at roomtemperature. Sodium triacetoxyborohydride (1.63 g, 7.7 mmol) was thenadded and the reaction was held at room temperature for 2 hours. Thereaction mixture was partitioned between saturated aqueous sodiumhydrogencarbonate solution (50 ml) and dichloromethane (50 ml). Theorganic phase was removed and the aqueous phase was washed withdichloromethane (50 ml). The combined organic phases were dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel eluting with asolvent gradient of dichloromethane:methanol:concentrated aqueousammonia (99:1:0.1, by volume, changing to 96:4:0.4). Product containingfractions were evaporated to afford the title compound as a white foam(2.56 g).

[0474]¹H NMR (400 MHz, CDCl₃): δ: 7.40-7.20 (6H, m), 7.10-6.90 (3H, m),6.20-5.95 (1H, m), 5.00-4.70 (1H, m), 4.55-4.40 (1H, m), 3.70 (2H, s),3.60-3.47 (2H, m), 3.45-3.25 (2H, m), 2.85-2.67 (4H, m), 2.65-2.40 (5H,m), 2.38-2.20 (2H, t), 2.18-1.20 (17H, m) ppm.

[0475] LRMS (electrospray): m/z [M+H]⁺ 588.

Preparation 38

[0476] tert-Butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate

[0477] A mixture of tert-butyl(1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate(Preparation 37) (2.55 g, 4.34 mmol), ammonium formate (2.73 g, 43.4mmol) and 20% w/w palladium hydroxide on carbon (0.25 g) in ethanol (35ml) was heated to 60° C. After one hour additional ammonium formate(0.63 g, 10.1 mmol) was added and heating continued at 60° C. for afurther two hours. The cooled reaction mixture was then filtered throughArbocel® and the filtrate evaporated under reduced pressure. The residuewas partitioned between dichloromethane (100 ml) and saturated aqueoussodium hydrogencarbonate solution (50 ml), the organic phase separatedand washed with water (30 ml). The organic layer was dried (MgSO₄) andsolvent evaporated under reduced pressure. The residue was purified byflash column chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol:concentrated aqueous ammonia(99:1:0.1 changing to 93:7:1). Product containing fractions wereevaporated to afford the title compound as a white foam (1.50 g).

[0478]¹H NMR (400 MHz, CDCl₃): δ: 7.35-7.25 (1H, m), 7.10-6.90 3H, m( ),6.20-5.80 (1H, m), 4.95-4.65 (1H, m), 4.60-4.40 (1H, m), 3.85 (2H, s),3.45-3.30 (2H, m), 3.20-3.10 (2H, m), 2.75-2.65 (2H, m), 2.60-2.40 (5H,m), 2.35-1.20 (20H, m) ppm.

[0479] LRMS (electrospray): m/z [M+H]⁺ 498.

Preparation 39

[0480] Methyl1-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0481] Methyl chloroformate (0.167 g, 1.76 mmol) was added to a solutionof tert-butyl(1S)-3-[3-endo-(2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propylcarbamate(Preparation 38) (0.80 g, 1.60 mmol) in dichloromethane (10 ml) undernitrogen at room temperature. The reaction was stirred at roomtemperature for 1.5 hours and then washed with saturated aqueous sodiumhydrogencarbonate solution (10 ml). The organic phase was removed andthe aqueous layer extracted with more dichloromethane (2×10 ml). Thecombined dichloromethane extracts were dried (MgSO₄) and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with a solvent mixture ofdichloromethane:methanol:concentrated aqueous ammonia (99:1:0.1 changingto 93:7:1). Product containing fractions were evaporated to afford thetitle compound as a white foam (0.84 g).

[0482]¹H NMR (400 MHz, CDCl₃): δ: 7.35-7.25 (1H, m), 7.10-6.90 (3H, m),6.10-5.80 (1H, m), 4.95-4.75 (1H, m), 4.60-4.35 (3H, m), 3.85-3.60 (5H,m), 3.45-3.25 (2H, m), 2.75-2.65 (2H, m), 2.60-1.05 (24H, m) ppm.

[0483] LRMS (electrospray): m/z [M+H]⁺ 556.

Preparation 40

[0484] Methyl1-endo-{8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatetrihydrochloride

[0485] Hydrogen chloride gas was bubbled through a solution of methyl1-endo-(8-{(3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate(Preparation 39) (0.83 g, 1.50 mmol) in dichloromethane (15 ml) at 0° C.until the solution was saturated. The reaction mixture was then allowedto warm to room temperature and stirred for one hour. Solvent wasevaporated under reduced pressure and the residue suspended indichloromethane (10 ml). This process was repeated three times to givethe title compound as a white solid (0.82 g).

[0486]¹H NMR (400 MHz, d₆-DMSO): δ: 11.30-11.10 (1H, br s), 9.10-8.80(3H, br s), 7.55-7.40 (3H, m), 7.25-7.20 (1H, t), 5.80-5.60 (1H, m),4.55-4.40 (3H, m), 4.20-4.00 (2H, m), 3.80-3.05 (10H, m), 3.00-1.90(13H, m) ppm.

[0487] LRMS (electrospray): m/z [M+H]⁺ 456.

Preparation 41

[0488] Ethyl (3S)-3-(acetamido)-3-(3-fluorophenyl)propanoate

[0489] Acetyl chloride (7.9 ml, 111 mmol) in dichloromethane (50 ml) wasadded dropwise to a cold (0° C.) solution of ethyl(3S)-3-amino-3-(3-fluorophenyl)propanoate (WO99/31099, Scheme 3 page 97)(25.2 g, 102 mmol) in dichloromethane (200 ml). The reaction was stirredfor 2 hours at 0° C., then water (100 ml) was added. The reactionmixture was adjusted to pH1 with 2 N hydrochloric acid and the organiclayer separated. The dichloromethane layer was washed with saturatedsodium hydrogencarbonate solution (50 ml), water (50 ml) and then dried(MgSO4). Solvent was evaporated under reduced pressure to afford a thickoil which was purified by column chromatography (silica gel, elutingwith diethyl ether) to give the title compound as a clear, colourlessoil, 25.1 g.

[0490] LRMS: m/z 254 (MH+).

Preparation 42

[0491] N-[(1S)-1-(3-Fluorophenyl)-3-hydroxypropyl]acetamide

[0492] A stirred suspension of ethyl(3S)-3-(acetylamino)-3-(3-fluorophenyl)propanoate (2.5 g, 9.9 mmol) andsodium borohydride (0.76 g, 20 mmol) in THF (20 ml) was heated at 50° C.under a nitrogen atmosphere. Methanol (1.8 ml) was then carefully addeddropwise and the reaction mixture heated under reflux for one hour. Thereaction was allowed to cool to room temperature then water (10 ml) andaqueous sodium hydroxide solution (1.5 g NaOH in 4 ml water) carefullyadded dropwise. The solution was extracted with ethyl acetate (3×30 ml)and the combined organic extracts dried (MgSO4) and evaporated to givethe title compound as a white solid (2.08 g).

[0493] LRMS (electrospray): m/z [M+H]+ 212.

Preparation 43

[0494] N-[(1S)-1-(3-Fluorophenyl)-3-oxopropyl]acetamide

[0495] Pyridine sulfur trioxide complex (37.7 g, 237 mmol) was addedportionwise over 20 minutes to a stirred cold (0° C.) solution ofN-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]acetamide (25 g, 118 mmol),DMSO (16.5 ml, 233 mmol) and triethylamine (33 ml, 237 mmol) indichloromethane (240 ml). After two hours stirring at room temperature,solvent was evaporated under reduced pressure and the residue applieddirectly to a silica gel column. Eluting with a gradient system startingwith ethyl acetate:dichloromethane (50:50 by volume) then ethylacetate:dichloromethane (80:20 by volume) and finally ethyl acetate gavethe title compound as a colourless oil which solidified on standing(13.9 g).

[0496] 1H NMR (400 MHz, CDCl3): δ: 9.75 (1H, s), 7.30 (1H, m), 7.10-6.90(3H, m), 6.40 (1H, br s), 5.50 (1H, m), 3.05 (1H, dd), 2.90 (1H, dd),2.00 (3H, s) ppm.

[0497] LRMS (electrospray): m/z [M+H]+ 210.

Preparation 44

[0498] Endo-8-Benzyl-8-azabicyclo[3.2.1]oct-3-ylamine

[0499] Endo-8-Benzyl-8-azabicyclo[3.2.1]oct-3-ylamine dihydrochloridehemihydrate (100 g, 0.34 mol) was dissolved in water (300 ml) and ethylacetate (500 ml). The aqueous layer was adjusted to pH 10 by theaddition of 10M sodium hydroxide (70 ml), resulting in a 5° C. exotherm.The reaction was stirred at ambient temperature for 15 minutes and thelayers separated. The aqueous layer was washed with ethyl acetate (500ml). The organic layers were combined and washed with water (300 ml),and concentrated under reduced pressure to a pale yellow oil containingtraces of ethyl acetate, 64.9 g, 90% yield.

[0500] LRMS (Electrospray): m/z=217.2 (MH⁺)

Preparation 45

[0501]Endo-8-Benzyl-N-(3-nitro-4-pyridyl)-8-azabicyclo[3.2.1]oct-3-ylamine

[0502] 4-Ethoxy-3-nitropyridine.hydrochloride salt (135.3 g, 0.661 mol)was slurried in tert-amyl alcohol (390 ml) at ambient temperature undera nitrogen blanket. 1,8-Diazabicylco[5.4.0]undec-7-ene (192.1 g, 1.26mol) was added to the reaction mixture, followed by a solution of thetitle compound from preparation 44 (130 g, 0.601 mol) in tert-amylalcohol (260 ml). The resultant solution was heated to reflux for 4.5hours. The solution was cooled to ambient temperature and the resultantthick yellow slurry stirred at ambient temperature for 12 hours andfurther at 5° C. for 2 hours. The solid was filtered off and dried in anoven under reduced pressure at 50° C. overnight, to give the titlecompound, 132.8 g, 91% yield.

[0503] LRMS (Electrospray): m/z=339.3 (MH⁺)

Preparation 46

[0504]N4-(endo-8-Benzyl-8-azabicyclo[3.2.1]oct-3-yl)pyridine-3,4-diamine

[0505] The title compound from Preparation 45 (150.0 g, 0.123 mol) wasslurried in methanol (750 ml). 10 wt % of 5% Palladium on carbon (15.0g) was added. The mixture was stirred under an atmosphere of hydrogen at50 psi, 25° C. for 2.5 hours. A sample was taken and analysis by tlcshowed that the reaction was complete. The reaction was filtered throughArbocelTM (filtration aid) and the filter pad washed with methanol (750ml). The methanol was evaporated under reduced pressure and replacedwith ethyl acetate (1.5 L) to leave a total volume of 300 ml ethylacetate. The mixture was granulated at ambient temperature for 2 hoursand further at 0° C. for 1 hour. The solid was filtered off and washedwith ethyl acetate (75 ml) and dried in an oven under reduced pressure,at 50° C. overnight, to give the title compound as a white solid, 105.6g, 78%.

[0506] LRMS (Electrospray): m/z=309.3 (MH⁺)

Preparation 47

[0507]1-(endo-8-Benzyl-8azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-imidazo[4,5-c]pyridine

[0508] The title compound from Preparation 46 (32.0 g, 0.103 mol) wasslurried in toluene (96 ml) at ambient temperature under a nitrogenblanket. Acetic anhydride (64 ml) and acetic acid (160 ml) were addedresulting in a 10° C. exotherm. The mixture was heated to refluxovernight. A sample was taken for analysis by tlc, which showed thereaction was complete. The reaction solution was allowed to cool toambient temperature. The acetic acid and toluene were removed underreduced pressure to give a brown oil. The oil was dissolved indichloromethane (320 ml) and water (160 ml) to give a two-phasesolution. The aqueous layer was adjusted to pH 10 by the addition of 10Msodium hydroxide. The layers were separated and the aqueous layer washedwith dichloromethane (160 ml). The organics were combined, washed withwater (240 ml) and concentrated under reduced pressure, replacing withethyl acetate (320 ml) to leave approximately 96 ml ethyl acetate. Theresultant slurry was granulated at 0° C. for 15 minutes. Heptane (96 ml)was added, and the mixture was granulated at 0° C. for 2 hours. Thebeige solid was collected by filtration, washed with 1:1 ethylacetate/heptane (32 ml) and dried in an oven under reduced pressure, at50° C. overnight, to give the title compound, 30 g, 88%.

[0509] LRMS (Electrospray): m/z=333.3 (MH⁺)

Preparation 48

[0510] Methyl1-(endo-8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0511] The title compound from Preparation 47 (59.0 g, 0.177 mol) wasslurried in ethanol (280 ml) and water (15 ml) at ambient temperatureunder a nitrogen blanket. The mixture was cooled to −70° C. Methylchloroformate (16.5 ml, 0.213 mol) was added over 10 minutes maintainingthe temperature below −50° C. The reaction was cooled to −70° C. andstirred for 45 minutes. Lithium borohydride was added as a 2M solutionin tetrahydrofuran (107 ml, 0.213 mol) over 15 minutes, maintaining thetemperature below −40° C. A sample was taken for analysis by tlc, whichshowed the reaction wad complete. The mixture was allowed to warm to−20° C. During this time gas evolution was observed. Water (295 ml) wasadded allowing the mixture to warm to ambient temperature and stir for15 minutes. Dichloromethane (590 ml) was added and the resultanttwo-phase solution separated. The aqueous layer was re-extracted withdichloromethane (295 ml). The organics were combined and washed withsaturated sodium chloride solution (148 ml). The dichloromethane wasremoved under reduced pressure, replacing with ethyl acetate (590 ml) toleave a total volume of 118 ml ethyl acetate. The resultant slurry wasgranulated at ambient temperature for 1.5 hours, then further at 0° C.for 1 hour. The solid was collected by filtration, washed with ethylacetate (30 ml) and dried in an oven under reduced pressure at 50° C.overnight, to give the title compound as an off white solid, 61.6 g,89%.

[0512] LRMS (Electrospray): m/z=393.4 (MH⁺)

Preparation 49

[0513] Methyl1-(endo-8-azabicyclo[3.2.1]oct-3yl)2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0514] The title compound from Preparation 48 (161.7 g, 0.412 mol) wasslurried in methanol (1.62 L) at ambient temperature. 10 wt % of 5%Palladium on carbon (16.2 g) was added. The mixture was stirred under anatmosphere of hydrogen at 50 psi, 50° C., overnight. A sample was takenfor analysis by tlc, which showed that the reaction was complete. Thereaction mixture was filtered through ArbocelTM (filtration aid) and thefilter pad washed with methanol (1.0 L). The methanol was removed underreduced pressure, replacing with ethyl acetate (1.62 L) thenconcentrated to dryness, to give the title compound as a pale yellowoil, 118.6 g, 95%.

[0515] LRMS (Electrospray): m/z=305.3 (MH⁺)

Preparation 50

[0516] Ethyl(S)-3-[benzyloxycarbonyl)amino]-3-(3-fluorophenyl)propanoate

[0517] Ethyl (S)-3-amino-3-(3-fluorophenyl)propanoate hydrochloride (1.0kg, 4.04 mol) was slurried in ethyl acetate (5.0 L) at ambienttemperature. Saturated sodium carbonate solution (5.0 L) and water (5.0L) were added. The resultant two-phase solution was cooled to 10° C.Benzyl chloroformate (605 ml, 1.05 mol) was added to the mixturemaintaining the temperature below 20° C. The mixture was stirred at 20°C. for 20 minutes. A sample was taken and analysed by HPLC, which showedthe reaction was complete. The aqueous layer was adjusted to pH 9 by theaddition of saturated sodium carbonate. The phases were separated. Theaqueous layer was extracted further with ethyl acetate (5.0 L). Theorganics were combined and washed with water (5.0 L). The ethyl acetatewas removed under reduced pressure to give the title compound as a waxywhite solid, 1.39 kg, 100%.

[0518] LRMS (Electrospray): m/z=346.3 (MH⁺)

Preparation 51

[0519] Benzyl (S)-1-(3-fluorophenyl)-3-hydroxypropylcarbamate

[0520] The title compound from Preparation 50 (13.95 g, 0.404 mol) wasdissolved in tetrahydrofuran (98 ml) at ambient temperature under anitrogen blanket. Sodium borohydride was added, resulting in a 10° C.exotherm. The reaction was heated to 50° C. and methanol added (3.3 ml,0.0808 mol) over 5 minutes maintaining the temperature at 50° C. Someoff gassing and frothing was observed. The reaction was heated to refluxfor 1.5 hours. A sample was taken and analysed by HPLC, which showedthat the reaction was complete. The mixture was cooled to ambienttemperature. 2M sodium hydroxide (98 ml) was added and the resultanttwo-phase solution stirred for 15 minutes. The phases were separated.The aqueous layer was further extracted with tetrahydrofuran (50 ml).The organics were combined and washed with saturated sodium chloridesolution (70 ml). The tetrahydrofuran was removed under reduced pressureand replaced with ethyl acetate (70 ml). The ethyl acetate solution wasconcentrated to dryness under reduced pressure to azeotropically removeany remaining water. The title compound was isolated as a white waxysolid,

[0521] LRMS (Electrospray): m/z=304.2 (MH⁺)

Preparation 52

[0522] Benzyl (S)-1-(3-fluorophenyl)-3-hydroxypropylcarbamate

[0523] The title compound from Preparation 51, (165.0 g, 0.72 mol) wasdissolved in ethyl acetate (1.65 L) at ambient temperature under anitrogen blanket. Water (803 ml), sodium bicarbonate (175 g, 2.10 mol),TEMPO (1.13 g, 0.0072 mol) and sodium bromide (76.1 g, 0.74 mol) wereadded. The mixture was cooled to 5° C. Sodium hypochlorite solution(1.62M, 469 ml, 0.76 mol) was added over 1 hour maintaining thetemperature below 10° C. The two-phase mixture was stirred for 20minutes. A sample was taken for analysis by tlc, which showed thereaction was complete. The phases were separated. The aqueous layer wasextracted further with ethyl acetate (401 ml). The organics werecombined and washed with 10 wt % potassium hydrogen sulfate solution(803 ml), followed by 10 wt % sodium thiosulfate solution (401 ml) andsaturated sodium chloride solution (401 ml). Frothing and off gassingobserved during the potassium hydrogen sulfate wash. The ethyl acetatewas removed under reduced pressure to yield the title compound as ayellow oil, 139.3 g, 89%.

[0524] LRMS (Electrospray): m/z=302.2 (MH⁺)

Preparation 53

[0525] Methyl1-(endo-8-{(3S)-3-[benzyloxycarbonyl)amino]-3-(3-fluorophenyl)propyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylate

[0526] The title compound from Preparation 49 (3.20 g, 0.0105 mol) andsodium triacetoxyborohydride (3.35 g, 0.0158 mol) were slurried in ethylacetate (35 ml) at ambient temperature under a nitrogen blanket. Thetitle compound from Preparation 52 (3.48 g, 0.0116 mol) was added as asolution in tetrahydrofuran (7 ml) over 15 minutes. The mixture wasstirred overnight. A sample was taken for analysis by tlc, which showedthat the reaction was complete. 2M sodium hydroxide (14 ml) was addedover 5 minutes. The aqueous layer of the resultant two-phase solutionwas adjusted to pH 10, by the addition of 10M sodium hydroxide (7.5 ml).The phases were separated. The organic layer was washed with water (17.5ml). The ethyl acetate was removed under reduced pressure to give thetitle compound as a yellow oil, 5.3 g, 77%.

[0527] LRMS (Electrospray): m/z=590.5 (MH⁺)

Preparation 54

[0528] Methyl1-{endo-8-[(3S)-3-amino-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]pyridine-5-carboxylate

[0529] The title compound from Preparation 53 was dissolved in methanol(26.5 ml). 10 wt % Palladium hydroxide (0.53 g) was added. The mixturewas stirred under an atmosphere of hydrogen at 50 psi, at ambienttemperature for 4 hours. A sample was taken and tlc analysis showed thatthe reaction was complete. The reaction mixture was filtered throughArbocelTM (filtration aid) and the filter pad washed with methanol (26.5ml). The methanol was evaporated under reduced pressure to give thetitle compound as a yellow oil, 3.81 g, 93%.

[0530] LRMS (Electrospray): m/z=456.4 (MH⁺)

[0531] Biological Activity

[0532] The ability of the compounds of formula (I) to inhibit binding ofHIV envelope protein (gp120) to CCR5 receptors was determined by theprocedure described in Example 1 of EP 1 118 858 A2. The compounds offormula (I) exhibited potent activity (nanomolar (nM) IC₅₀ values) inthis assay.

[0533] In particular, in this assay the compounds of Examples 9 and 30both had an IC₅₀ of 7 nM; the compound of Example 17 had an IC₅₀ of 15nM; the compound of Example 33 had an IC₅₀ of 23 nM; and the compound ofExample 44 had an IC₅₀ of 14 nM.

[0534] Powder X-Ray Diffraction (PXRD) Data

[0535] Methyl1-{endo-8-[(3S)-3-acetamido-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carboxylatemonohydrate

[0536] The PXRD pattern for the title compound, prepared in the samemanner as the compound of Example 44, was obtained using a Siemens D5000diffractometer (λ=1.54178 Å) over the 2θ angular range 2-55° with a0.02° step size. Data was collected at each step for 5 seconds. Peakpositions were determined by use of silicon powder (15% wt.) as aninternal reference standard (Table 1). TABLE 1 PXRD Peak Data for thetitle compound 2-Theta Intensity ° % 7.141 3.0 9.087 11.3 11.666 5.212.719 25.4 13.027 23.4 14.107 11.9 14.475 29.4 15.530 15.4 15.935 20.717.191 7.7 17.522 11.6 17.923 41.2 18.137 21.9 19.096 40.9 19.589 10.220.624 100.0 21.516 47.6 22.208 21.6 23.210 36.1 23.419 27.5 24.310 12.324.968 13.6 26.241 25.7 26.674 13.9 26.959 12.9 27.505 5.4 27.937 7.428.397 11.4 28.737 15.0 29.179 24.3 30.007 21.1 30.947 5.4 31.941 11.032.631 17.7 33.402 5.6 34.808 9.0 36.010 8.3 36.910 10.6 37.746 9.638.454 6.4 39.117 12.5 41.619 10.4 41.857 11.3 43.324 8.0 44.002 8.845.309 10.8 47.667 7.1 49.618 8.4 51.032 7.0 52.670 7.2

[0537] The PXRD patterns for the compounds of both Examples 44 and 45were consistent with the above PXRD data.

Examples 46-49

[0538] The PXRD pattern simulations involving 2-theta angles andrelative intensities were calculated from single crystal structuresusing the Cerius² Diffraction-Crystal Module. The simulation parameterswere:

[0539] Wavelength=1.54178 Å

[0540] Polarisation Factor=0.5

[0541] Crystallite Size=500×500×500 Å

[0542] Lorentzian Peak Shape

[0543] The main peaks (in degrees 2-theta) of the simulated PXRDpatterns are listed in tables (2-5). TABLE 2 Simulated PXRD Peak Datafor the compound of Example 46 2-Theta Intensity ° % 6.768 76.1 10.07621.7 10.671 36.9 11.054 17.3 13.079 8.7 13.801 6.4 15.807 5.6 16.55221.4 16.975 80.7 17.331 25.5 17.848 38.9 18.422 55.2 18.880 100.0 19.42424.7 20.070 98.8 20.799 39.1 21.100 21.9 21.581 58.5 22.527 23.0 22.89430.2 23.341 45.6 23.740 6.0 24.723 8.2 25.225 18.4 25.498 17.2 25.96622.2 26.312 8.6 26.782 13.3 26.976 16.9 27.494 7.3 27.941 16.5 28.64120.3 28.944 7.8 29.302 8.3 29.950 6.7 30.460 17.5 31.088 9.6 31.695 5.632.905 8.1 33.362 10.1 33.520 9.7 35.040 9.1 35.551 8.4 37.152 5.837.380 5.9 38.287 9.4 38.457 8.2 38.937 12.3 39.495 7.0 39.929 5.740.793 5.0 42.526 5.2 42.986 7.5 44.638 5.2 47.791 6.5

[0544] TABLE 3 Simulated PXRD Peak Data for the compound of Example 472-Theta Intensity ° % 6.859 22.5 8.823 8.9 10.277 16.1 10.516 14.911.541 22.6 12.802 8.5 13.851 4.3 14.260 7.8 16.418 27.4 16.950 74.017.688 6.5 18.377 11.3 18.881 34.0 19.342 100.0 19.860 16.4 20.644 19.421.281 23.6 21.586 14.9 21.860 5.7 22.672 29.7 23.179 5.4 23.522 16.124.906 12.7 25.259 5.1 25.602 4.0 27.245 4.7 28.000 4.8 28.431 23.028.913 12.3 29.552 13.4 31.333 8.5 32.057 4.3 32.221 4.4 32.685 7.833.593 8.4 33.792 6.7 34.511 6.6 36.022 6.5 36.456 7.1 39.229 5.7 45.1145.2 51.277 4.2

[0545] TABLE 4 Simulated PXRD Peak Data for the compound of Example 482-Theta Intensity ° % 6.870 33.0 8.908 6.4 10.463 14.8 10.761 9.0 11.6565.3 12.966 4.1 14.787 5.9 16.422 6.5 16.720 21.0 17.026 60.7 18.400 6.918.893 100.0 19.591 26.1 20.103 31.3 20.790 18.3 21.570 32.3 22.094 4.322.823 15.3 23.207 23.7 23.849 6.9 24.909 12.4 25.531 5.1 25.720 4.026.301 7.1 26.571 8.6 27.922 4.7 28.174 6.2 28.612 6.1 29.016 6.6 29.4946.9 30.387 13.3 30.642 9.6 31.231 4.4 31.551 7.2 32.016 6.8 32.824 4.433.478 6.4 34.280 4.7 34.483 7.2 34.750 5.6 37.504 6.1 39.705 5.2 42.7975.2 43.416 4.5

[0546] TABLE 5 Simulated PXRD Peak Data for the compound of Example 492-Theta Intensity ° % 6.842 41.9 10.061 32.0 10.637 41.0 11.082 23.913.212 9.4 13.772 10.3 15.818 11.1 16.640 14.3 17.233 74.4 17.583 44.517.812 42.4 18.426 42.3 18.824 100.0 19.352 15.7 19.648 24.3 20.053 87.520.736 38.1 21.016 20.3 21.233 19.4 21.616 47.3 22.707 24.8 23.300 29.623.500 20.9 23.920 9.3 24.060 12.5 24.680 10.6 25.651 16.6 25.990 17.826.613 8.9 27.052 19.3 27.171 16.9 27.442 6.3 28.073 13.4 28.661 27.129.231 10.5 29.941 7.2 30.155 5.8 30.568 11.8 30.740 7.3 31.177 7.631.761 7.1 33.104 6.3 33.450 9.7 33.894 6.7 35.038 5.6 35.373 5.7 35.60310.1 37.352 7.1 38.531 5.9 38.843 8.6 39.387 5.1 39.766 7.4 39.971 7.340.734 5.5 43.118 7.1 45.533 5:3 46.554 6.6 51.453 5.3

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate or derivatives thereofwherein: X and Y are selected from CH₂ and NR⁴ such that one of X and Yis CH₂ and the other is NR⁴; R¹ and R⁴ are independently R⁵; COR⁵;CO₂R⁵; CONR⁶R⁷; SO₂R⁵; or (C₁₋₆ alkylene)phenyl, wherein phenyl issubstituted by 0 to 3 atoms or groups selected from C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, halogen, CF₃, OH, CN,NR⁶R⁷, COR⁷, CO₂R⁷ or CONR⁶R⁷; R² is phenyl substituted by 0 to 3 atomsor groups selected from C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy,C₁₋₆ alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁶R⁷, CO₂R⁷ or CONR⁶R⁷; R³is C₁₋₄ alkyl substituted by 0 to 3 fluorine atoms; R⁵ is C₁₋₆ alkyl;C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₃₋₇ cycloalkyl; a 5 or 6-membered aromaticheterocycle; or a 4 to 7-membered saturated heterocycle; wherein saidalkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atomsor groups selected from oxo, halogen, CF₃, OR⁷, CN, NR⁶R⁷, COR⁷, CO₂R⁷or CONR⁶R⁷; wherein said heterocylces contain one to three heteroatomsselected from N, O or S; and wherein said heterocylces are substitutedby 0 to 3 atoms or groups selected from C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁶R⁷, COR⁷,CO₂R⁷ or CONR⁶R⁷; R⁶ is H or R⁵; R⁷ is H or C₁₋₆ alkyl; or, when R⁶ andR⁷ are both attached to the same N atom, NR⁶R⁷ may also represent a 5 to7 membered, saturated, partially unsaturated or aromatic, heterocyclecontaining from 0 to 2 additional heteroatoms selected from O, N or S.2. A compound as defined in claim 1 wherein X is CH₂, NH, NC₁₋₄ alkyl,NCH₂phenyl, NCOC₁₋₄ alkyl substituted by 0 to 3 fluorine atoms, NCO₂C₁₋₄alkyl or NSO₂C₁₋₂ alkyl.
 3. A compound as defined in claim 1 wherein Xis CH₂, NCOC₁₋₂ alkyl substituted by 0 or 3 fluorine atoms or NCO₂C₁₋₄alkyl.
 4. A compound as defined in any preceding claim wherein X is CH₂,NCOC₁₋₂ alkyl or NCO₂C₁₋₂ alkyl.
 5. A compound as defined in anypreceding claim wherein Y is CH₂, NH, NC₁₋₆ alkyl, N(C₁₋₆alkylene)phenyl, NCOC₁₋₆ alkyl substituted by 0 to 3 fluorine atoms,NCO₂C₁₋₆ alkyl or NSO₂C₁₋₆ alkyl.
 6. A compound as defined in anypreceding claim wherein Y is CH₂, NH, NC₁₋₄ alkyl, N(C₁₋₄alkylene)phenyl, NCOC₁₋₄ alkyl substituted by 0 to 3 fluorine atoms,NCO₂C₁₋₄ alkyl or NSO₂C₁₋₄ alkyl.
 7. A compound as defined in anypreceding claim wherein Y is CH₂, NH, NC₁₋₄ alkyl, NCH₂phenyl, NCOC₁₋₄alkyl substituted by 0 or 3 fluorine atoms, NCO₂C₁₋₄ alkyl or NSO₂C₁₋₂alkyl.
 8. A compound as defined in any preceding claim wherein Y is CH₂,NCOC₁₋₂ alkyl, or NCO₂C₁₋₂ alkyl.
 9. A compound as defined in anypreceding claim wherein R¹ is COR⁵ or CO₂R⁵ and R⁵ is, C₁₋₆ alkylsubstituted by 0 to 3 fluorine atoms, C₃₋₇ cycloalkyl substituted by 0to 3 fluorine atoms, C₁₋₆ alkoxy substituted by 0 to 3 fluorine atoms,or a 4 to 7-membered saturated heterocycle containing 1 to 3 heteroatomsselected from N, O or S.
 10. A compound as defined in any precedingclaim wherein R¹ is COR⁵ or CO₂R⁵, wherein R⁵ is C₁₋₄ alkyl substitutedby 0 to 3 fluorine atoms, C₃₋₅ cycloalkyl substituted by 0 to 3 fluorineatoms, or a 5 or 6-membered, N, O or S containing, saturatedheterocycle.
 11. A compound as defined in any preceding claim wherein R¹is COR⁵ or CO₂R⁵ and R⁵ is C₁₋₃ alkyl substituted by 0 or 3 fluorineatoms, C₃₋₄ cycloalkyl, or a 5 or 6-membered, O-containing, saturatedheterocycle.
 12. A compound as defined in any preceding claim wherein R¹is COC₁₋₂ alkyl or CO₂C₁₋₂ alkyl.
 13. A compound as defined in anypreceding claim wherein R² is phenyl substituted by 0 or 3 fluorineatoms.
 14. A compound as defined in any preceding claim wherein R² isphenyl substituted by 0 or 1 fluorine atoms.
 15. A compound as definedin any preceding claim wherein R² is mono-fluoro-substituted phenyl. 16.A compound as defined in any preceding claim wherein R³ is C₁₋₄ alkyl.17. A compound as defined in any preceding claim wherein R³ is methyl.18. A pharmaceutical composition including a compound of the formula (I)or a pharmaceutically acceptable salt, solvate or derivative thereof,according to any preceding claim, together with one or morepharmaceutically acceptable excipients, diluents or carriers
 19. Apharmaceutical composition according to claim 18 including one or moreadditional therapeutic agents.
 20. A compound of the formula (I) or apharmaceutically acceptable salt, solvate or derivative thereofaccording to any of claims 1 to 17 for use as a medicament.
 21. The useof a compound of the formula (I) or of a pharmaceutically acceptablesalt, solvate or derivative thereof as claimed in any one of claims 1 to17 for the manufacture of a medicament for the treatment of a disorderin which the modulation of CCR5 receptors is implicated.
 22. Useaccording to claim 21 wherein the disorder is HIV, a retroviralinfection genetically related to HIV, AIDS, or an inflammatory disease.23. A method of treatment of a mammal suffering from a disorder in whichthe modulation of CCR5 receptors is implicated which comprises treatingsaid mammal with an effective amount of a compound of formula (I) or apharmaceutically acceptable salt, solvate or derivative thereofaccording to any of claims 1 to
 17. 24. A method of treatment accordingto claim 23 wherein the disorder is HIV, a retroviral infectiongenetically related to HIV, AIDS, or an inflammatory disease.
 25. Acompound of formula (VII), (IX), (XI) or (XIX) wherein X, Y and R³ areas defined in claim 1 for a compound of formula (I), and Pg is an aminoprotecting group.


26. A compound of formula (II), (IV), (V), (VI), (XVII), (XXII), (XXIV),(XXV) or (XXVI), wherein X, Y, R¹, R² and R³ are as defined in claim 1for a compound of formula (I), and Pg is an amino protecting group.